rs137852331

Positions:

chrX-154534489-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP5_Very_Strong

The NM_001360016.2(G6PD):c.493A>G(p.Asn165Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,210,034 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000036 ( 0 hom. 1 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 4.92

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 10 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, 5 uncertain in NM_001360016.2

PP5

Variant X-154534489-T-C is Pathogenic according to our data. Variant chrX-154534489-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534489-T-C is described in Lovd as [Pathogenic]. Variant chrX-154534489-T-C 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.493A>G	p.Asn165Asp	missense_variant	6/13	ENST00000393562.10
G6PD	NM_000402.4 linkuse as main transcript	c.583A>G	p.Asn195Asp	missense_variant	6/13
G6PD	NM_001042351.3 linkuse as main transcript	c.493A>G	p.Asn165Asp	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.493A>G	p.Asn165Asp	missense_variant	6/13	1	NM_001360016.2	P4	P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112302

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34514

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:

0.00113

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000495

AC:

AN:

181972

Hom.:

AF XY:

0.0000598

AC XY:

AN XY:

66848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000650

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000364

AC:

AN:

1097732

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000868

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112302

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34514

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00113

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency (PS4_M, PP4); for one, heterozygous mother also has deficiency (PP1). Decreased activity in red blood cells (7-25%) (PS3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by Eurofins (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 165 of the G6PD protein (p.Asn165Asp). This variant is present in population databases (rs137852331, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 1562739, 7789945, 8118045, 18270558). This variant is also known as "Taipei" or "Chinese-3". ClinVar contains an entry for this variant (Variation ID: 10393). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects G6PD function (PMID: 8118045). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 hemolytic anemia (favism) (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 asparagine to aspartic acid. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (8 heterozygotes, 0 homozygote, 4 hemizygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated Glucose-6-phosphate dehydrogenase, NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is known as the Taipei variant, and has been reported in multiple hemizygous and heterozygous individuals with G6PD deficiency and/or episodic acute haemolytic anaemia (ClinVar, PMID: PMID: 1562739, PMID: 36150187, PMID: 30045279). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Significantly reduced enzyme activity has been demonstrated in patients with this variant (PMID: 36150187, PMID: 30045279). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 01, 2016

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

Malaria, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 08, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 14, 2014

- -

G6PD TAIWAN-HAKKA 2

Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

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

FATHMM_MKL

Uncertain

0.93

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.53

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

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.7

L;L;L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.44

Sift4G

Benign

0.066

T;.;T;T;.;.;.

Polyphen

0.0060

B;B;B;.;.;.;.

Vest4

0.69

MutPred

0.85

Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;.;Loss of sheet (P = 0.1398);

MVP

0.97

MPC

0.25

ClinPred

0.14

GERP RS

5.7

Varity_R

0.94

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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