rs137852321

Positions:

• chrX-154532694-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):​c.1160G>A​(p.Arg387His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,885 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.41

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant X-154532694-C-T is Pathogenic according to our data. Variant chrX-154532694-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532694-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1160G>A	p.Arg387His	missense_variant	10/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1250G>A	p.Arg417His	missense_variant	10/13		NP_000393.4
G6PD	NM_001042351.3	c.1160G>A	p.Arg387His	missense_variant	10/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1160G>A	p.Arg387His	missense_variant	10/13	1	NM_001360016.2	ENSP00000377192	P4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097885 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363303

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency and CNSHA (PS4_M, PP4). Decreased activity in red blood cells (0-4%) (PS3). Within dimer interface (PM1). Predicted to be damaging or deleterious by multiple computational algorithms (PP3). Not found in gnomAD (PM2). Reported as pathogenic by Invitae (PP5). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg387 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been observed in individuals with G6PD-related conditions (PMID: 1611091), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed in individual(s) with G6PD deficiency (PMID: 2602358, 12187030, 29248304, Invitae). ClinVar contains an entry for this variant (Variation ID: 10376). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 387 of the G6PD protein (p.Arg387His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. -

Malaria, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 09, 2022

- -

G6PD BEVERLY HILLS 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	0.58
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.5	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.0	.;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.043	D;.;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.79
MutPred		0.81		Gain of ubiquitination at K386 (P = 0.0898);Gain of ubiquitination at K386 (P = 0.0898);Gain of ubiquitination at K386 (P = 0.0898);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.93

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

Other links and lift over

dbSNP: rs137852321; hg19: chrX-153760909;