rs34193178

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001360016.2(G6PD):c.1048G>C(p.Asp350His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,210,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 63 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., 32 hem., cov: 24)

Exomes 𝑓: 0.00012 ( 0 hom. 31 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:4

Conservation

PhyloP100: 7.29

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:

G6PD (HGNC:):

G6PD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18980572).

BS2

High Hemizygotes in GnomAd4 at 32 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2 linkuse as main transcript	c.1048G>C	p.Asp350His	missense_variant	9/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 linkuse as main transcript	c.1138G>C	p.Asp380His	missense_variant	9/13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 linkuse as main transcript	c.1048G>C	p.Asp350His	missense_variant	9/13		NP_001035810.1	P11413-1A0A384NL00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 linkuse as main transcript	c.1048G>C	p.Asp350His	missense_variant	9/13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

116

AN:

112465

Hom.:

Cov.:

AF XY:

0.000924

AC XY:

AN XY:

34621

show subpopulations

Gnomad AFR

AF:

0.00358

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.000399

AC:

AN:

182804

Hom.:

AF XY:

0.000252

AC XY:

AN XY:

67436

show subpopulations

Gnomad AFR exome

AF:

0.00403

Gnomad AMR exome

AF:

0.000620

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000124

AC:

136

AN:

1098182

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

363554

show subpopulations

Gnomad4 AFR exome

AF:

0.00352

Gnomad4 AMR exome

AF:

0.000682

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:

0.00000119

Gnomad4 OTH exome

AF:

0.000390

GnomAD4 genome

AF:

0.00103

AC:

116

AN:

112519

Hom.:

Cov.:

AF XY:

0.000923

AC XY:

AN XY:

34685

show subpopulations

Gnomad4 AFR

AF:

0.00358

Gnomad4 AMR

AF:

0.000465

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.00123

ESP6500AA

AF:

0.00235

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2021	- -
Pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	G6PD: BS2 -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Sep 01, 2024	Reported in two hemizygotes with normal G6PD activity in red blood cells (BS3), and in a hemizygote with G6PD deficiency but activity not stated (PP4). Predicted to have reduced function (PP3). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

G6PD deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 12, 2022

Variant summary: G6PD c.1138G>C (p.Asp380His) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) 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 0.00046 in 204594 control chromosomes, including 23 hemizygotes (gnomAD). c.1138G>C, also known as the "Mira d'Aire" variant, has been reported in the literature in individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Bulliamy_1997, Manco_2007, Powers_2018). These reports do not provide unequivocal conclusions about association of the variant with Glucose 6 Phosphate Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.65

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D;D;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

.;.;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

M;M;M;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.5

.;.;D;D

REVEL

Pathogenic

0.82

Sift

Benign

0.035

.;.;D;D

Sift4G

Uncertain

0.019

D;.;D;D

Polyphen

0.95

P;P;P;.

Vest4

0.71

MVP

1.0

MPC

2.2

ClinPred

0.97

GERP RS

4.0

Varity_R

0.79

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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