rs72554664

Positions:

chrX-154532257-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_001360016.2(G6PD):c.1388G>A(p.Arg463His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,209,616 control chromosomes in the GnomAD database, including 1 homozygotes. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 1 hom. 34 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16O:5

Conservation

PhyloP100: 7.34

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_pathogenic. Variant got 7 ACMG points.

PP5

Variant X-154532257-C-T is Pathogenic according to our data. Variant chrX-154532257-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 100059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532257-C-T is described in Lovd as [Pathogenic]. Variant chrX-154532257-C-T is described in Lovd as [Pathogenic]. Variant chrX-154532257-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.043610394). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2 linkuse as main transcript	c.1388G>A	p.Arg463His	missense_variant	12/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 linkuse as main transcript	c.1478G>A	p.Arg493His	missense_variant	12/13		NP_000393.4	P11413-3
G6PD	NM_001042351.3 linkuse as main transcript	c.1388G>A	p.Arg463His	missense_variant	12/13		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.1388G>A	p.Arg463His	missense_variant	12/13	1	NM_001360016.2	ENSP00000377192.3		P11413-1

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

111763

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

33983

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:

0.00534

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:

0.000554

AC:

101

AN:

182202

Hom.:

AF XY:

0.000477

AC XY:

AN XY:

67028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00717

Gnomad SAS exome

AF:

0.0000528

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.000112

AC:

123

AN:

1097804

Hom.:

Cov.:

AF XY:

0.0000936

AC XY:

AN XY:

363230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00358

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000170

AC:

AN:

111812

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

34042

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00535

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000428

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 23, 2024	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 arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (71 heterozygotes, 1 homozygote, 33 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (0 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glucose-6-phosphate dehydrogenase, C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as the Kaiping variant, it is one the most common pathogenic alleles amongst the Chinese population; and is classified as a WHO class II variant (severe deficiency) (PMID: 33051526). In addition, it is consistently classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 1207 - Parental origin of the variant is unresolved (duo analysis, father not tested). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia, jaundice, and favism, and one with CNSHA (PS4_M, PP4). Segregates with deficiency in a family (PP1). Decreased activity in red blood cells (1-44%) and when expressed in E. coli (PS3). Predicted to be disease causing by Mutation Taster and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 6563, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 463 of the G6PD protein (p.Arg463His). This variant is present in population databases (rs72554664, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been described as a common cause of glucose-6-phosphate dehydrogenase deficiency in southeast Asia, although it has also been reported in affected individuals from other populations (PMID: 9589612, 30315739, 17726510, 21446359, 15906717, 15223006, 20236109). This variant is also known as Kaiping. ClinVar contains an entry for this variant (Variation ID: 100059). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 04, 2022	This sequence change in G6PD is predicted to replace arginine with histidine at codon 463, p.(Arg463His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the C-terminal glucose-6-phosphate dehydrogenase domain. There is a small physicochemical difference between arginine and histidine. The highest population minor allele frequency in gnomAD v2.1 is 0.7% (104/14,782 alleles, 1 homozygote, 32 hemizygotes) in the East Asian population. This variant is the most common cause of glucose-6-phosphate dehydrogenase (G6PD) deficiency in China (also known as Kaiping). It has been detected in hemizygous in affected males and compound heterozygous with a second pathogenic variant or homozygous in affected females. Individuals with this variant display reduced G6PD activity in their cells, with female heterozygous carriers demonstrating moderate deficiency (PMID: 33051526). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 19, 2024	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 16, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2024	Observed in hemizygous state in several unrelated patients referred for genetic testing at GeneDx and in published literature and not observed in hemizygous state in controls (PMID: 18270558, 14505231, 9891846); 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: 15625830, 8935319, 23313052, 25440321, 20236109, 7390473, 29783823, 15766741, 7327562, 18270558, 11793482, 12497642, 15316963, 18046504, 34659341, 21931771, 29339739, 18329300, 24958328, 25775246, 26829728, 29702993, 29783822, 15223006, 17587269, 23006493, 15727905, 21874587, 16155737, 16331553, 16528451, 15476167, 17018380, 16513531, 16329560, 11295127, 16927025, 22938511, 14505231, 1953767, 9891846, 28376293, 31628766, 33069889, 32959227, 34953813, 36071769, 35611242, 29251006, 35193651, 35313968, 12215013, 34272389) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 01, 2021	The G6PD c.1388G>A; p.Arg463His variant (rs72554664), also known as G6PD Kaiping, is reported in the literature as a common G6PD deficiency variant in Asian populations (Chiu 1991, Fu 2018, Li 1998, Nuchprayoon 2002). This variant is reported in ClinVar (Variation ID: 100059), and is found in the East Asian population with an allele frequency of 0.70% (104/14782 alleles, including 32 hemizygotes and a single homozygote) in the Genome Aggregation Database. The arginine at codon 463 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.1387C>T; p.Arg463Cys, c.1387C>A; p.Arg462Ser) have been reported in individuals with G6PD deficiency (Hirono 1997, Rodrigues 2002). Based on available information, the p.Arg463His variant is considered to be pathogenic. References: Chiu DT et al. Two commonly occurring nucleotide base substitutions in Chinese G6PD variants. Biochem Biophys Res Commun. 1991 180(2):988-93. 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. Hirono A et al. Molecular analysis of eight biochemically unique glucose-6-phosphate dehydrogenase variants found in Japan. Blood. 1997 Jun 15;89(12):4624-7. Li P et al. Analysis of common mutations and associated haplotypes in Chinese patients with glucose-6-phosphate dehydrogenase deficiency. Biochem Mol Biol Int. 1998 46(6):1135-43. Nuchprayoon I et al. Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common deficiency variant in the Thai population. Hum Mutat. 2002 Feb;19(2):185. Rodrigues MO et al. Glucose-6-phosphate dehydrogenase deficiency in Portugal: biochemical and mutational profiles, heterogeneity, and haplotype association. Blood Cells Mol Dis. 2002 Mar-Apr;28(2):249-59. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	G6PD: PS3, PM1, PP1:Moderate, PP3, PS4:Supporting -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PS4+PP4+PS3+PM5_Supporting -

G6PD deficiency

Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001042351.1:c.1388G>A in the G6PD gene has an allele frequency of 0.007 in East Asian subpopulation in the gnomAD database. This variant has been described as a common cause of glucose-6-phosphate dehydrogenase deficiency in Southeast Asia, although it has also been reported in affected individuals from other populations (PMID: 9589612, 30315739, 17726510, 21446359, 15906717, 15223006, 20236109). Experimental studies have shown that this missense change causes a significant reduction in enzyme activity and affinity for glucose-6-phosphate (PMID: 16607506). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFTT. aken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PS4; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 25, 2023	The G6PD c.1478G>A (p.Arg493His) variant, also known as c.1388G>A (p.Arg463His), or G6PD Kaiping, is a missense variant. In the literature, this variant is reported as one of the most common pathogenic variants associated with glucose-6-phosphate dehydrogenase deficiency in the East Asian population (PMID: 36949502; 33051526). The highest frequency of this allele in the Genome Aggregation Database is 0.007036 in the East Asian population (version 2.1.1). This frequency is high but is consistent with disease prevalence estimates. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as pathogenic by at least twelve submitters in ClinVar. Based on the available evidence, the c.1478G>A (p.Arg493His) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2016

- -

Malaria, susceptibility to

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

G6PD DHON

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD SAPPORO-LIKE

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD ANANT

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD KAIPING

Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

G6PD PETRICH-LIKE

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

Benign

0.25

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.77

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;.

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.99

.;.;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.044

T;T;T;T

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.3

M;M;M;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.5

.;.;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

.;.;D;D

Sift4G

Uncertain

0.035

D;.;D;D

Polyphen

0.99

D;D;D;.

Vest4

0.77

MutPred

0.85

Loss of phosphorylation at T466 (P = 0.1664);Loss of phosphorylation at T466 (P = 0.1664);Loss of phosphorylation at T466 (P = 0.1664);.;

MVP

1.0

MPC

2.3

ClinPred

0.26

GERP RS

5.7

Varity_R

0.92

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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