rs137852342

Positions:

chrX-154532969-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001360016.2(G6PD):c.1024C>T(p.Leu342Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000215 in 1,210,867 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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 0.000044 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000019 ( 0 hom. 5 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3O:1

Conservation

PhyloP100: 5.29

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 -1 ACMG points.

PP5

Variant X-154532969-G-A is Pathogenic according to our data. Variant chrX-154532969-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10405.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2, Likely_pathogenic=3}. Variant chrX-154532969-G-A is described in Lovd as [Pathogenic]. Variant chrX-154532969-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.13903645). . Strength limited to SUPPORTING due to the PP5.

BS2

High Hemizygotes in GnomAdExome4 at 5 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.1024C>T	p.Leu342Phe	missense_variant	9/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 linkuse as main transcript	c.1114C>T	p.Leu372Phe	missense_variant	9/13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 linkuse as main transcript	c.1024C>T	p.Leu342Phe	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.1024C>T	p.Leu342Phe	missense_variant	9/13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112603

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34767

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:

0.00140

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:

0.000137

AC:

AN:

183026

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

67564

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00166

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1098212

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363580

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000629

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000444

AC:

AN:

112655

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34829

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00141

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:3Uncertain:2

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia (PS4_M, PP4). Also found in two heterozygous sisters with deficiency who inherited this variant (c.1024C>T) from father and c.383T>C from mother (PP1). Decreased activity in red blood cells (2-39%) (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 12, 2021	This sequence change replaces leucine with phenylalanine at codon 342 of the G6PD protein (p.Leu342Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 8364584, 10502785, 16329560, 20203002, 30045279, 30315739). This variant is also known as C13184T or Chinese-5. ClinVar contains an entry for this variant (Variation ID: 10405). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PS4+PS3_Moderate+PM2_Supporting+PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2023	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 17, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 28, 2017	- -

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

May 28, 2024

- -

G6PD deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 15, 2024

Variant summary: G6PD c.1114C>T (p.Leu372Phe, also known as Chinese-5) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 183026 control chromosomes with 7 hemizygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00014 vs 0.29), allowing no conclusion about variant significance. c.1114C>T has been reported in the literature in many individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (example, Wang_2021, Fu_2018). These data indicate that the variant is very likely to be associated with disease. At least 7 studies report experimental evidence evaluating an impact on protein function using hemizygote cells, the average G6PD activity appeared to be 30-40% of normal activity (Geck_2023). The following publications have been ascertained in the context of this evaluation (PMID: 29339739, 36681081, 34659341). ClinVar contains an entry for this variant (Variation ID: 10405). Based on the evidence outlined above, the variant was classified as pathogenic. -

G6PD MAHIDOL-LIKE

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

Benign

0.25

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.61

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.84

D;D;D;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

.;.;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

L;L;L;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

.;.;N;N

REVEL

Pathogenic

0.70

Sift

Benign

0.14

.;.;T;T

Sift4G

Benign

0.18

T;.;T;T

Polyphen

0.69

P;P;P;.

Vest4

0.77

MVP

1.0

MPC

1.5

ClinPred

0.12

GERP RS

4.0

Varity_R

0.67

gMVP

0.98

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