rs137852341

Positions:

Variant summary

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

The NM_001360016.2(G6PD):c.392G>T(p.Gly131Val) variant causes a missense change. The variant allele was found at a frequency of 0.000019 in 1,210,297 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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: 0.000017 ( 0 hom. 2 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 4.68

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001360016.2

PP5

Variant X-154535261-C-A is Pathogenic according to our data. Variant chrX-154535261-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154535261-C-A is described in Lovd as [Pathogenic]. Variant chrX-154535261-C-A 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.392G>T	p.Gly131Val	missense_variant	5/13	ENST00000393562.10
G6PD	NM_000402.4 linkuse as main transcript	c.482G>T	p.Gly161Val	missense_variant	5/13
G6PD	NM_001042351.3 linkuse as main transcript	c.392G>T	p.Gly131Val	missense_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.392G>T	p.Gly131Val	missense_variant	5/13	1	NM_001360016.2	P4	P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

112094

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34286

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:

0.00112

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:

0.0000763

AC:

AN:

183370

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00101

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:

0.0000173

AC:

AN:

1098148

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

363506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000563

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000357

AC:

AN:

112149

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34351

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00112

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other: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 G6PD deficiency, some with anemia (PP4, PS4_M). Decreased activity in red blood cells of hemizygotes (0-49%) (PS3). Predicted to be deleterious by REVEL and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 131 of the G6PD protein (p.Gly131Val). This variant is present in population databases (rs137852341, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 11243133, 11400791, 25775246). It is commonly reported in individuals of South East Asian ancestry (PMID: 11243133, 11400791, 25775246). This variant is also known as the Quing Yuan or Chinese-4 variant. ClinVar contains an entry for this variant (Variation ID: 10404). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 22, 2023	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 24, 2021

- -

Malaria, susceptibility to

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 18, 2021

The G6PD c.392G>T; p.Gly131Val variant (rs137852341), also known as Chinese-4, is described in the literature in several individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (Chiu 1993, Peng 2015. Additionally, this variant displays only 20 percent enzymatic activity compared to the wildtype protein (Chiu 1993), and is considered a class III variant (Fu 2018). This variant is also reported in ClinVar (Variation ID: 10404), and is found in the East Asian population with an allele frequency of 0.10% (15/14841 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The glycine residue is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.855). Based on available information, this variant is considered to be pathogenic. References: Chiu DT et al. Molecular characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients of Chinese descent and identification of new base substitutions in the human G6PD gene. Blood. 1993 81(8):2150-4. PMID: 8471773. Fu C et al. Newborn screening of glucose-6-phosphate dehydrogenase deficiency in Guangxi, China: determination of optimal cutoff value to identify heterozygous female neonates. Sci Rep. 2018 Jan 16;8(1):833. PMID: 29339739. Peng Q et al. Large cohort screening of G6PD deficiency and the mutational spectrum in the Dongguan District in Southern China. PLoS One. 2015 10(3):e0120683. PMID: 25775246. -

G6PD QUING YUAN

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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

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

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.74

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.2

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

REVEL

Pathogenic

0.85

Sift

Benign

0.037

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

Sift4G

Uncertain

0.046

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

Polyphen

0.99

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

Vest4

0.72

MVP

0.99

MPC

0.80

ClinPred

0.50

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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