rs78478128

Positions:

• chrX-154536168-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001360016.2(G6PD):​c.131C>G​(p.Ala44Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,209,580 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 65 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 6.38

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant X-154536168-G-C is Pathogenic according to our data. Variant chrX-154536168-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 10406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154536168-G-C is described in Lovd as [Pathogenic]. Variant chrX-154536168-G-C is described in Lovd as [Likely_benign]. Variant chrX-154536168-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.131C>G	p.Ala44Gly	missense_variant	3/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.221C>G	p.Ala74Gly	missense_variant	3/13		NP_000393.4
G6PD	NM_001042351.3	c.131C>G	p.Ala44Gly	missense_variant	3/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.131C>G	p.Ala44Gly	missense_variant	3/13	1	NM_001360016.2	ENSP00000377192	P4

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 111652 Hom.: 0 Cov.: 23 AF XY: 0.000237 AC XY: 8 AN XY: 33820

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00492

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000169 AC: 31 AN: 183304 Hom.: 0 AF XY: 0.000295 AC XY: 20 AN XY: 67784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 121 AN: 1097872 Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 65 AN XY: 363234

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000412

GnomAD4 genome AF: 0.000116 AC: 13 AN: 111708 Hom.: 0 Cov.: 23 AF XY: 0.000236 AC XY: 8 AN XY: 33886

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00493

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000126 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.221C>G (p.Ala74Gly) variant in G6PD gene has been reported in heterozygous state in individuals affected with hemolytic anemia. This variant has been reported to be a common cause of the glucose-6-phosphate dehydrogenase in South Asia, although it has also been reported in other populations (Sukumar et al., 2004). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995). This variant is reported with the allele frequency 0.01% in the gnomAD and 0.02% in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic / Uncertain Significance. The amino acid Ala at position 74 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala74Gly in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 44 of the G6PD protein (p.Ala44Gly). This variant is present in population databases (rs78478128, gnomAD 0.2%), 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: 10192449, 17524386). It is commonly reported in individuals of South Asian ancestry (PMID: 8533762, 15315792, 20621077, 22906047, 26829728, 27880809). ClinVar contains an entry for this variant (Variation ID: 10406). 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: 8533762). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jun 22, 2024	A heterozygous missense variation in exon 3 of the G6PD gene that results in the amino acid substitution of Glycine for Alanine at codon 44 was detected. The observed variant c.131C>G (p.Ala44Gly) has a minor allele frequency of 0.03%, 0.01%, 0.02% and 0.003% in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1) and topmed databases, respectively. The insilico predictions of the variant are probably damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2022	- -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with anemia and jaundice (PP4, PS4_M). In one family, hemiygote and heterozygous mother both have decreased G6PD activity (PP1). Decreased activity in red blood cells (5-33%) (PS3). In GxxGDLA NADP binding site (PM1). Predicted to be damaging by SIFT and MutationTaster, and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	This variant in exon 3 of the G6PD gene results in the amino acid substitution from Alanine to Glycine at codon 74 (p.Ala74Gly) with the sequence change of c.221C>G (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The reference base is conserved across the species and in-silico predictions by SIFT and MutationTaster are damaging. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. The G6PD c.221C>G; p.Ala74Gly variant, also referred to as c.131C>G; p.Ala44Gly, commonly known as G6PD Orissa, has been described in literatures as a Class III variant, associated with moderate enzyme deficiency (Arunachalam et al., 2020; PMID: 32425388, Minucci et al., 2010; PMID: 20621077). This variant has previously been reported for glucose-6-phosphate dehydrogenase deficiency and is most frequent in Indian tribal population (Kaeda et al., 1995; PMID:8533762, Sukumar et al., 2004; PMID:15315792, Lin et al., 2016; PMID:26829728, Sarker et al., 2016; PMID:27880809). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995; PMID:8533762). -

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	Jun 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	G6PD: PM1:Strong, PM5, PS3:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2023	Functional analysis of recombinant enzyme showed significantly increased Km-NADP and increased thermostability (Kaeda et al., 1995); Also known as G6PD Orissa (Kaeda et al., 1995; Sarker et al., 2016); This variant is associated with the following publications: (PMID: 21507207, 27880809, 21931771, 8533762, 30097005, 20621077, 15315792, 2255919, 26829728, 26139767, 26021654, 12497642, 21446359, 33069889, 12215013) -

Malaria, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2024

- -

G6PD deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 03, 2023

The G6PD c.221C>G (p.Ala74Gly) missense variant, also known as c.131C>G (p.Ala44Gly) or the G6PD Orissa allele, has been commonly reported in individuals with glucose-6-phosphate dehydrogenase deficiency with South Asian ancestry, including in a hemizygous and homozygous state (PMID: 27880809; 8533762; 32425388). Enzyme activity in individuals with this variant is typically 5%-20% of normal. The highest frequency of this allele in the Genome Aggregation Database is 0.004917 in the South Asian population, which includes eight hemizygotes (version 3.1.2). This frequency is consistent with disease prevalence estimates. Functional studies of purified enzyme have demonstrated that this variant causes an increase in Km for NADP+, which results in a reduced G6PD enzyme activity level (PMID: 8533762). This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.221C>G (p.Ala74Gly) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency. -

G6PD ORISSA 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	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	.;.;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.36
MutPred		0.95		Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);Gain of disorder (P = 0.0537);
MVP		1.0
MPC		0.71
ClinPred		0.45	T
GERP RS		5.4
Varity_R		0.98
gMVP		0.94

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

Other links and lift over

dbSNP: rs78478128; hg19: chrX-153764383;