rs137852322

Positions:

• chrX-154532701-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):​c.1153T>C​(p.Cys385Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C385F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 8.75

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 18 ACMG points.

• PM1: In a hotspot region, there are 9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532700-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1722616.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-154532701-A-G is Pathogenic according to our data. Variant chrX-154532701-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532701-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1153T>C	p.Cys385Arg	missense_variant	10/13	ENST00000393562.10
G6PD	NM_000402.4	c.1243T>C	p.Cys415Arg	missense_variant	10/13
G6PD	NM_001042351.3	c.1153T>C	p.Cys385Arg	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1153T>C	p.Cys385Arg	missense_variant	10/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

G6PD TOMAH Pathogenic:1 Other:1

other, no assertion criteria provided	literature only	OMIM	Apr 18, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 09, 2017	This variant has previously been described as pathogenic including in a patient with chronic non-spherocytic haemolytic anaemia (PMID: 2602358). Functional characterization of the variant demonstrated severely reduced function (PMID: 2602358). The variant is not present in public reference databases, and is thus presumed rare. The residue is conserved within vertebrates, and the substitution of an arginine residue is predicted to be damaging by in silico methods. There are additional reports of different amino acid substitutions at this residue also as pathogenic (PMID: 9410474, 9332310, 28028996). This variant was found in the hemizygous state, and was maternally inherited. Based on the available evidence, the variant is classified as pathogenic. -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1

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 (1-11%) (PS3). Within dimer interface (PM1). Predicted to be pathogenic or deleterious by several in silico tools (PP3). Not found in gnomAD (PM2). Post_P 0.999 (odds of pathogenicity 6568, Prior_P 0.1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D;D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.86	.;.;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.1	.;.;D;D
REVEL	Pathogenic	0.84
Sift	Benign	0.089	.;.;T;T
Sift4G	Benign	0.27	T;.;T;T
Polyphen		0.98	D;D;D;.
Vest4		0.85
MutPred		0.83		Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);Gain of MoRF binding (P = 0.0219);.;
MVP		1.0
MPC		2.7
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.94
gMVP		0.99

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: rs137852322; hg19: chrX-153760916;