chrX-154534495-C-T

Position:

chrX-154534495-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_001360016.2(G6PD):c.487G>A(p.Gly163Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000038 in 1,209,982 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G163D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000036 ( 0 hom. 20 hem. )

Consequence

G6PD
NM_001360016.2 missense, splice_region

Scores

Splicing: ADA: 0.9163

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 7.18

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]

G6PD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001360016.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-154534494-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1722732.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant X-154534495-C-T is Pathogenic according to our data. Variant chrX-154534495-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534495-C-T is described in Lovd as [Pathogenic]. Variant chrX-154534495-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
G6PD	NM_001360016.2 linkuse as main transcript	c.487G>A	p.Gly163Ser	missense_variant, splice_region_variant	6/13	ENST00000393562.10
G6PD	NM_000402.4 linkuse as main transcript	c.577G>A	p.Gly193Ser	missense_variant, splice_region_variant	6/13
G6PD	NM_001042351.3 linkuse as main transcript	c.487G>A	p.Gly163Ser	missense_variant, splice_region_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.487G>A	p.Gly163Ser	missense_variant, splice_region_variant	6/13	1	NM_001360016.2	P4	P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000534

AC:

AN:

112400

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34574

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.00181

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

181825

Hom.:

AF XY:

0.0000449

AC XY:

AN XY:

66749

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000364

AC:

AN:

1097582

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

363042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.000443

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.0000534

AC:

AN:

112400

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34574

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000283

Gnomad4 SAS

AF:

0.00181

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:9

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with jaundice, favism, and anemia (PS4_M, PP4). Decreased activity in red blood cells (0-30%) (PS3). Predicted to be damaging by SIFT and PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	This variant in exon 6 of the G6PD gene results in the amino acid substitution from Glycine to Serine at codon 193 (p.Gly193Ser) with the sequence change of c.577G>A (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. The observed variant has a minor allele frequency of 0.00004400% in gnomAD database. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This is a Class II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. The G6PD c.577G>A; p.Gly193Ser variant, also referred to as c.487G>A; p.Gly163Ser. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by (Sarker SK et al., 2016 PMID: 27880809; Li Q et al., 2015 PMID: 26226515; Narang A et al., 2020 PMID: 32906206.) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The hemizygous p.Gly193Ser variant in G6PD was identified by our study in one individual with non-spherocytic hemolytic anemia due to G6PD deficiency. This variant has been identified in 0.03657% (7/19142) of South Asian chromosomes, including 3 hemizygous individuals, and 0.01442% (2/13869) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852314). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, most individuals with non-spherocytic hemolytic anemia due to G6PD deficiency are asymptomatic. This variant has been reported pathogenic in ClinVar (Variation ID: 10367). The p.Gly193Ser variant in G6PD has been reported in 75 Southeast Asian individuals with G6PD Deficiency in the literature (PMID: 27880809, 2503817, 11499668, 15349799). The prevalence of this variant in affected individuals is significantly increased compared to the prevalence in large population studies, supporting pathogenicity. In vitro functional studies provide some evidence that the p.Gly193Ser variant may impact protein stability, activity, (PMID: 17959407, 8118045). In summary, the p.Gly193Ser variant is pathogenic. ACMG/AMP Criteria applied: PP3, PS3, PS4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 07, 2023	The G6PD c.487G>A variant is classified as Pathogenic (PS3_Moderate, PS4, PM1, PM5, PP3) The G6PD c.487G>A variant is located in a splice region. The G6PD c.487G>A variant is a single nucleotide change in exon 6/13 of the G6PD gene, which is predicted to change the amino acid glycine at position 163 in the protein to serine. The variant is commonly reported in patients with a clinical presentation of Glucose-6-phosphate dehydrogenase deficiency and haemolytic anaemia (HGMD:CM890050) (PS4). A molecular modelling of G6PD(p.Gly163Ser) was performed based on the X-ray structure of human G6PD. It is suggested that Ser-163 might affect the stability of G6PD alpha-helix d and beta-strand E, besides the conformation of beta-strand D. In conclusion, the biochemical and structural properties of G6PD(p.Gly163Ser) and G6PD(WT) enzymes are significantly different, which may be responsible for clinical diversity of G6PD deficiencies. (Lu et al, 2011; PMID: 22165289) (PS3_moderate). This variant is located in the conserved binding domain of the G6PD protein (PM1). This variant is a missense change at an amino acid residue where the different missense change p.Gly163Asphas been seen before (PMID:8364584) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs137852314) and in the HGMD database: CM890050. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 10367). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient haemolytic anemia (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected, however some heterozygous female carriers can also be affected depending on X inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 for a recessive condition (5 heterozygotes, 3 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated NAD binding domain (Pfam). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative missense change to aspartic acid has been described in individuals with severe G6PD deficiency (WHO class I; PMID: 27880809). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most common pathogenic G6PD variants in Thai and Burmese populations (WHO class II or III; ClinVar, PMID: 22171972, PMID: 25536053) (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant results in impaired folding and reduced protein stability (PMID: 17959407). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the G6PD protein (p.Gly163Ser). This variant is present in population databases (rs137852314, gnomAD 0.04%). This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase deficiency (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). It is commonly reported in individuals of South Asian ancestry (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). This variant is also known as G6PD Mahidol. ClinVar contains an entry for this variant (Variation ID: 10367). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects G6PD function (PMID: 8118045, 17959407, 22165289). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	Apr 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2023	Published functional studies demonstrate G163S is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding properties (Huang et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20007901, 22165289, 29548282, 33069889, 34272389, 31323480, 11793482, 12215013, 36212142, 34659341, 33637102, 21989994, 27880809, 2503817, 29240263, 28356147, 28138089, 11499668, 1924316, 8956035, 15349799, 4435794, 1562739, 31589614, 34953813, 30097005, 17959407, 29251006, 28376293) -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 09, 2017

- -

Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malaria, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 20, 2024

- -

G6PD deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 08, 2022

Variant summary: G6PD c.577G>A (p.Gly193Ser) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 181825 control chromosomes. c.577G>A, also known as G6PD Mahidol has been widely reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency and is considered among one of the most frequent mutations described among individuals of Vietnamese ancestry (example, Bancone_2019). These data indicate that the variant is very likely to be associated with disease. Mahidol variant has been shown to cause low or very low enzymatic activity in RBCs and is associated with relatively high hemolytic risk by 8-aminoquinolines treatment (cited in Bancone_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

G6PD MAHIDOL

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.68

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;.;D;.;D

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;.;D;D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;M;M;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.3

.;.;D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Benign

0.048

.;.;D;D;D;D;D

Sift4G

Uncertain

0.032

D;.;D;D;.;.;.

Polyphen

0.98

D;D;D;.;.;.;.

Vest4

0.87

MutPred

0.93

Loss of catalytic residue at I162 (P = 0.1428);Loss of catalytic residue at I162 (P = 0.1428);Loss of catalytic residue at I162 (P = 0.1428);Loss of catalytic residue at I162 (P = 0.1428);.;.;Loss of catalytic residue at I162 (P = 0.1428);

MVP

0.99

MPC

0.70

ClinPred

0.55

GERP RS

5.7

Varity_R

0.88

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over