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rs1050828

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 10P and 9B. PM1PP5_Very_StrongBP4BA1

The NM_001360016.2(G6PD):c.202G>A(p.Val68Met) variant causes a missense change. The variant allele was found at a frequency of 0.00644 in 1,210,144 control chromosomes in the GnomAD database, including 328 homozygotes. There are 2,070 hemizygotes in GnomAD Genomes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.033 ( 155 hom., 999 hem., cov: 23)
Exomes 𝑓: 0.0037 ( 173 hom. 1071 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

3
6
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:32U:1O:3

Conservation

PhyloP100: 3.75
Variant links:
Genes affected
G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2
PP5
Variant X-154536002-C-T is Pathogenic according to our data. Variant chrX-154536002-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154536002-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-154536002-C-T is described in Lovd as [Pathogenic]. Variant chrX-154536002-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.0068126023).. Strength limited to SUPPORTING due to the PP5.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
G6PDNM_001360016.2 linkuse as main transcriptc.202G>A p.Val68Met missense_variant 4/13 ENST00000393562.10
G6PDNM_000402.4 linkuse as main transcriptc.292G>A p.Val98Met missense_variant 4/13
G6PDNM_001042351.3 linkuse as main transcriptc.202G>A p.Val68Met missense_variant 4/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
G6PDENST00000393562.10 linkuse as main transcriptc.202G>A p.Val68Met missense_variant 4/131 NM_001360016.2 P4P11413-1

Frequencies

GnomAD3 genomes
AF:
0.0335
AC:
3748
AN:
112041
Hom.:
155
Cov.:
23
AF XY:
0.0291
AC XY:
995
AN XY:
34237
show subpopulations
Gnomad AFR
AF:
0.116
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0121
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000368
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00417
Gnomad NFE
AF:
0.000207
Gnomad OTH
AF:
0.0305
GnomAD3 exomes
AF:
0.00906
AC:
1661
AN:
183313
Hom.:
59
AF XY:
0.00575
AC XY:
390
AN XY:
67811
show subpopulations
Gnomad AFR exome
AF:
0.116
Gnomad AMR exome
AF:
0.00401
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000367
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000183
Gnomad OTH exome
AF:
0.00221
GnomAD4 exome
AF:
0.00368
AC:
4043
AN:
1098048
Hom.:
173
Cov.:
31
AF XY:
0.00295
AC XY:
1071
AN XY:
363416
show subpopulations
Gnomad4 AFR exome
AF:
0.131
Gnomad4 AMR exome
AF:
0.00489
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000296
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000653
Gnomad4 OTH exome
AF:
0.00703
GnomAD4 genome
AF:
0.0335
AC:
3754
AN:
112096
Hom.:
155
Cov.:
23
AF XY:
0.0291
AC XY:
999
AN XY:
34302
show subpopulations
Gnomad4 AFR
AF:
0.116
Gnomad4 AMR
AF:
0.0121
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000369
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000207
Gnomad4 OTH
AF:
0.0301
Alfa
AF:
0.00603
Hom.:
191
Bravo
AF:
0.0384
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.117
AC:
449
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00997
AC:
1211
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:32Uncertain:1Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:16Other:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJun 20, 2018This sequence change replaces valine with methionine at codon 68 of the G6PD protein (p.Val68Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs1050828, ExAC 11%). ClinVar contains an entry for this variant (Variation ID: 37123).  This variant is also known as the Asashi variant or p.Val98Met in the literature. This variant frequently co-occurs with the c.376A>G (p.Asn126Asp) variant (rs1050829) in cis (on the same chromosome), which is known as the G6PD A- haplotype c.[202G>A; 376A>G] . The G6PD A- haplotype is the most prevalent G6PD deficiency variant in African populations which is present at 0.2% (PMID: 1303173, 24505519, 2572288, 4359638). ClinVar contains an entry for the G6PD A- haplotype (Variation ID: 10361). This variant has been reported to co-occur with another G6PD variant independent of the A- haplotype in a Japanese family affected with G6PD deficiency (PMID: 11852882). It has also been identified as homozygous independent of the A- haplotype in individuals suspected with G6PD deficiency (PMID: 23006493). While this variant alone has been shown to only mildly affect enzyme activity, the c.[202G>A; 376A>G] changes of the G6PD A- haplotype have been reported to act synergistically to cause dramatic reduction of the stability and enzymatic activity of the G6PD protein (PMID: 3393536, 1303173, 10734064, 6015571, 2836867, 16356170). For these reasons, this variant on the c.[202G>A; 376A>G] haplotype has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 27, 2016The p.Val98Met variant in G6PD (frequently reported as p.Val68Met on transcript NM_001042351.1) is a well-established pathogenic variant for G6PD deficiency and has been shown to alter G6PD enzyme activity (Hirono 2002, Shah 2014). This var iant has also been identified in 11% (955/8415) of African chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs105082 8). The variant's high frequency is consistent with the prevalence of G6PD defic iency in African populations and is thought to be a result of a partial protecti on against malaria (Manjurano 2012). The p.Val98Met variant is most frequently f ound in association with the common p.Asn156Asp allele. This combination indicat es the G6PD A- allele, which is a class III variant with a moderate level of def iciency (10-60% activity). In summary, the p.Val98Met meets criteria to be class ified as pathogenic for G6PD deficiency in an X-linked manner. -
Pathogenic, criteria provided, single submitterclinical testingCounsylOct 15, 2015- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJun 28, 2016The c.202G>A (p.Val68Met) missense variant is recognized as a disease-causing variant in the G6PD gene. Functional studies demonstrate reduced enzymatic activity of the G allele compared to WT. The prevalence of the variant in affected individuals (homozygous) is increased compared with the prevalence in controls and there is familial co-segregation with disease (Bwayo et al. 2013; Manjurano et al. 2012; Maiga et al. 2014; Shah et al. 2014; Pisani et al. 2012; Vulliamy et al. 1988; Odievre et al. 2011). Although the frequency of this variant in the African population within ExAC (http://exac.broadinstitute.org) is high it is consistent with observed and expected based on disease incidence (11.34%). Computational algorithms predict the variant has a damaging or deleterious effect. This variant is has been classified as pathogenic by multiple reputable clinical testing laboratories (Emory, Division of Human Genetics at Children’s Hospital of Philadelphia). In summary, this variant c.202G>A (p.Val68Met) meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 26, 2022- -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityDec 08, 2023While G6PD c.202G>A in isolation (called Asahi variant) has occasionally been identified in individuals with G6PD deficiency, it has more commonly been reported to co-occur on the same haplotype with another variant c.376A>G; p.Asn126Asp (complex variant c.376A>G/c.202G>A is called A- variant) and this complex variant has also been observed in individuals with G6PD deficiency. However, G6PD c.376A>G in isolation is considered a non-deficient variant that does not cause disease, and has instead been shown to act as a genetic modifier, increasing the risk of G6PD deficiency by two-fold in individuals heterozygous for c.202G>A3. Functional studies support that the A- variant results in clinically significant G6PD enzyme deficiency. c.202G>A (rs1050828) is present in a large population dataset (gnomAD v2.1.1: 2365/205030 total alleles; 1.2%; 641 hemizygotes and 90 homozygotes), and has been reported in ClinVar (Variation ID 37123). We consider c.202G>A in G6PD to be pathogenic. -
Pathogenic, criteria provided, single submittercurationDunham Lab, University of WashingtonAug 12, 2022Variant found in three unrelated families, where hemizygotes present with deficiency, some with hyperbilirubinemia, jaundice, and anemia (PS4_M, PP4). Two son-and-mother pairs both have variant and decreased activity, and sons have additional symptoms (PP1). Decreased activity in red blood cells (3-71%) and when expressed in E. coli (PS3). Predicted to be damaging by SIFT and probably damaging by PolyPhen (PP3). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.994 (odds of pathogenicity 1516, Prior_P 0.1). -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityAug 25, 2019- -
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasOct 30, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 12, 2022This variant was identifiedas hemizygous and togehter with NM_001042351.3:c.376A>G._x000D_ Criteria applied: PS4, PS3_SUP, PP3 -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanyNov 02, 2021- -
Pathogenic, no assertion criteria providedcurationDepartment Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos UniversityDec 30, 2017- -
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Uncertain significance and reported on 10-30-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, no assertion criteria providedclinical testingClinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)Apr 01, 2023- -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaFeb 20, 2015This heterozygous variant (c.202G>A; p.Val68Met) has been reported under the name of “Asahi variant” when no other variants are present on the same haplotype; the enzymatic activity was reduced to 41% of wild type. This variant have been previously published as part of the same haplotype (A- variant) which results in reduced enzymatic activity to 10-23% of normal activity. -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinDec 02, 2022ACMG classification criteria: PS3 supporting, PS4 strong, PP3 supporting -
not provided Pathogenic:10Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 23, 2022Results in 10-23% of normal G6PD activity and causes acute hemolytic anemia triggered by infections, certain drugs, and fava beans (Vulliamy et al., 1988; Beutler et al., 1989; Shah et al., 2014); This variant is associated with the following publications: (PMID: 12524354, 24943486, 21153663, 1889820, 22307442, 21931771, 8733135, 25182376, 23144702, 2836867, 11852882, 21479984, 25201310, 27884173, 2572288, 27853304, 28512736, 30609409, 31564435, 32387609, 1303173, 30577886, 31980526, 32641076, 33587123, 3393536, 34272389, 33069889, 33072997) -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenJun 23, 2022PS4, PP3, PP2, PS3 -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 24, 2015- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2023G6PD: PP1:Strong, PM1, PS4:Moderate, PP4, PS3:Supporting -
Uncertain significance, flagged submissionclinical testingBlueprint GeneticsNov 02, 2018- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 29, 2017- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsJul 02, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 04, 2022PS3, PS4 -
G6PD deficiency Pathogenic:2Other:1
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 11, 2021The G6PD c.292G>A (p.Val98Met) variant, which is also called c.202G>A (p.Val68Met), is a missense variant that has a well-characterized role in glucose-6-phosphate dehydrogenase (G6PD) deficiency, accounting for up to 25% of cases in sub-Saharan Africa. This variant has been reported in a large number of individuals with G6PD deficiency, including in a heterozygous, hemizygous, and homozygous state (Vulliamy et al. 1991; McDade et al. 2008; Tine et al. 2012; Dallol et al. 2012; Shah et al. 2014). It is commonly found in cis with the c.466A>G (p.Asn156Asp) variant, which is also known as c.376A>G (p.Asn126Asp), and this complex allele is often referred to as the A-(1) allele. The p.Val98Met variant is reported at a frequency of 0.116400 in the African/African American population of the Genome Aggregation Database (version 2.1.1), including in 90 homozygotes and 641 hemizygotes. This frequency is high but consistent with the prevalence of G6PD deficiency in this region and the potentially limited clinical expression of G6PD deficiency. Reduced enzyme activity of approximately 40% for heterozygotes and 80% for hemizygotes and homozygotes in red blood cells from individuals who carry the p.Val98Met variant only has been observed (Hirono et al. 2002; Shah et al. 2014). Based on the collective evidence, the p.Val98Met variant, is classified as pathogenic for G6PD deficiency. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 13, 2023Variant summary: G6PD c.292G>A (p.Val98Met) results in a conservative amino acid change located in the NAD-binding domain (IPR022674) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0091 in 183313 control chromosomes, predominantly at a frequency of 0.12 within the African or African-American subpopulation in the gnomAD database, including 59 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.0091 vs 0.29), and is consistent with the prevalence of G6PD deficiency in this region. Therefore, this allows no strong conclusion about variant significance. This variant is commonly observed as a complex variant (referred to as the A- haplotype) in cis with c.466A>G, p.Asn156Asp in individuals with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Dallol_2012, Shah_2014). c.292G>A has also been reported as a single variant, independent from the A- haplotype, in the literature in the hemizygous, homozygous, and heterozygous state in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency, including at least two unrelated cases of an affected hemizygous male with an affected heterozygous mother (e.g. Hirono_2002, Dallol_2012, Warang_2017, Powers_2018, Chen_2018). These data indicate that the variant is very likely to be associated with disease. Publications have reported experimental evidence evaluating an impact on protein function (e.g. Town_1992, Shah_2014). The most pronounced variant effect results in an approximately 40% reduction in enzyme activity for heterozygotes, and 80% for hemizygotes and homozygotes. Furthermore, this variant has been given a WHO classification of Class III: mild to moderate enzyme deficiency (10-60% residual activity). Twenty-three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority have classified the variant as pathogenic (n=19)/likely pathogenic (n=2), and two classified it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 02, 2018- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 12, 2020The c.[202G>A;376A>G] (p.[V68M;N126D]) complex allele affects exon 4 (coding exon 3) and exon 5 (coding exon 4) of the G6PD gene. This alteration results from a G to A substitution at nucleotide position 202, causing the valine (V) at amino acid position 68 to be replaced by a methionine (M), and from an A to G substitution at nucleotide position 376, causing the asparagine (N) at amino acid position 126 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD), the G6PD c.202G>A alteration was observed in 1.1% (2365/205030) total alleles studied, with a frequency of 11.6% (2208/18968) African alleles, including 89 homozygotes and 599 hemizygotes; the G6PD c.376A>G alteration was observed in 3.2% (6586/205081) total alleles studied, with a frequency of 31.8% (6025/18923) African alleles, including 714 homozygotes and 1605 hemizygotes. The G6PD c.[202G>A;376A>G] complex allele is also known as the “A-haplotype” and it is the most common G6PD-deficiency disease-causing allele in African populations. Of note, the c.376A>G (p.N126D) alteration is considered a benign variant when seen in isolation (Town, 1992; Shahjahani, 2013). A significant reduction in enzyme stability and activity has been observed when the c.202G>A (p.V68M) and c.376A>G (p.N126D) variants are present in cis (on the same chromosome) (Vulliamy, 1998; Town, 1992; Gómez-Gallego, 2000). Based on the available evidence, this alteration is classified as pathogenic. -
Malaria, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 31, 2023- -
Anemia, nonspherocytic hemolytic, due to G6PD deficiency;C2939465:G6PD deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterresearchUNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill-G6PD c.292G>A (p.V98M) and c.466A>G (p.N156D), often occur together in cis as part of a haplotype, referred to as the enzyme variant A- (PMID: 5448; 1303173). This variant is associated with glucose-6-phosphate dehydrogenase deficiency. -
G6PD ASAHI Other:1
other, no assertion criteria providedliterature onlyOMIMOct 24, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Uncertain
0.057
T
BayesDel_noAF
Pathogenic
0.41
Cadd
Uncertain
23
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;D;D;.;D;.;D
FATHMM_MKL
Uncertain
0.88
D
MetaRNN
Benign
0.0068
T;T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Pathogenic
3.4
M;M;M;M;.;.;.
MutationTaster
Benign
2.7e-7
P;P;P;P
PrimateAI
Uncertain
0.67
T
Sift4G
Uncertain
0.016
D;.;D;D;.;.;.
Polyphen
1.0
D;D;D;.;.;.;.
Vest4
0.43
MVP
0.98
MPC
0.51
ClinPred
0.057
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2
Varity_R
0.88
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1050828; hg19: chrX-153764217; COSMIC: COSV63703414; COSMIC: COSV63703414; API