rs137852346

Positions:

• chrX-154533634-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):​c.806G>A​(p.Cys269Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 3.69

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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-154533634-C-T is Pathogenic according to our data. Variant chrX-154533634-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154533634-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.806G>A	p.Cys269Tyr	missense_variant	8/13	ENST00000393562.10
G6PD	NM_000402.4	c.896G>A	p.Cys299Tyr	missense_variant	8/13
G6PD	NM_001042351.3	c.806G>A	p.Cys269Tyr	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.806G>A	p.Cys269Tyr	missense_variant	8/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in hemizygote with G6PD deficiency and CNSHA (PP4). Mother and sister have normal G6PD activity and do not carry variant, so presumed de novo (PM6). Undetectable activity in red blood cells and granulocytes (PS3). Not found in gnomAD (PM2). Post_P 0.988 (odds of pathogenicity 729.3, Prior_P 0.1). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 20, 2021	This sequence change replaces cysteine with tyrosine at codon 269 of the G6PD protein (p.Cys269Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 10666231). ClinVar contains an entry for this variant (Variation ID: 10412). This variant is not present in population databases (ExAC no frequency). -

G6PD AVEIRO Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 09, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.;D;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	.;.;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	.;.;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	.;.;D;D;D;D
Sift4G	Uncertain	0.0030	D;.;D;D;.;.
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.85
MutPred		0.91		Loss of catalytic residue at M267 (P = 0.0024);Loss of catalytic residue at M267 (P = 0.0024);Loss of catalytic residue at M267 (P = 0.0024);.;.;.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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: rs137852346; hg19: chrX-153761849;