rs1050828

Variant names:

• chrX-154536002-C-T
• rs1050828
• NM_001360016.2:c.202G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 15P and 9B. PS3 PM1 PP2 PP5_Very_Strong BP4 BA1

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. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000238425: 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." and additional evidence is available in ClinVar.

• 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:39 U:1 O:3
• Conservation: PhyloP100: 3.75
• Publications: 331 publications found

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]

G6PD Gene-Disease associations (from GenCC):

• anemia, nonspherocytic hemolytic, due to G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• class I glucose-6-phosphate dehydrogenase deficiency

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238425: 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.; SCV000494242: Functional studies demonstrate reduced enzymatic activity of the G allele compared to WT. 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.; SCV000711717: This variant has been shown to alter G6PD enzyme activity (Pal 2017 PMID: 28512736, Hirono 2002 PMID: 11852882, Hirono 1988 PMID: 2836867, Shah 2014 PMID: 25201310, Odièvre 2011 PMID: 21479984).; SCV002599322: Decreased activity in red blood cells (3-71%) and when expressed in E. coli (PS3).; SCV004239032: Functional studies support that the A- variant results in clinically significant G6PD enzyme deficiency.; SCV005905036: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 32387609).; SCV002034762: 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).; SCV003844610: 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.; SCV001445539: 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; Gómegz-Gallego, 2000).; SCV002599183: Decreased activity in red blood cells of hemizygotes (6-60%) (PS3).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001360016.2
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 185 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 2.0008 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, anemia, nonspherocytic hemolytic, due to G6PD deficiency.
• PP5: Variant X-154536002-C-T is Pathogenic according to our data. Variant chrX-154536002-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	NM_001360016.2	MANE Select	c.202G>A	p.Val68Met	missense	Exon 4 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.292G>A	p.Val98Met	missense	Exon 4 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.202G>A	p.Val68Met	missense	Exon 4 of 13	NP_001035810.1	P11413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.202G>A	p.Val68Met	missense	Exon 4 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.202G>A	p.Val68Met	missense	Exon 4 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.202G>A	p.Val68Met	missense	Exon 4 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 3748 AN: 112041 Hom.: 155 Cov.: 23

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

GnomAD2 exomes AF: 0.00906 AC: 1661 AN: 183313 AF XY: 0.00575

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 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

African (AFR) AF: 0.131 AC: 3458 AN: 26398

American (AMR) AF: 0.00489 AC: 172 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40505

Middle Eastern (MID) AF: 0.00435 AC: 18 AN: 4135

European-Non Finnish (NFE) AF: 0.0000653 AC: 55 AN: 841986

Other (OTH) AF: 0.00703 AC: 324 AN: 46091

GnomAD4 genome AF: 0.0335 AC: 3754 AN: 112096 Hom.: 155 Cov.: 23 AF XY: 0.0291 AC XY: 999 AN XY: 34302

African (AFR) AF: 0.116 AC: 3566 AN: 30814

American (AMR) AF: 0.0121 AC: 129 AN: 10642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6161

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.000207 AC: 11 AN: 53151

Other (OTH) AF: 0.0301 AC: 46 AN: 1527

Alfa AF: 0.0153 Hom.: 812

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
22	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (23)
11	1	-	not provided (12)
2	-	-	G6PD deficiency (3)
1	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency;C2939465:G6PD deficiency (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	not specified (1)
-	-	-	G6PD ASAHI (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	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
Mutation Taster		=37/63	polymorphism (auto)

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

Other links and lift over

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