rs137852325

Positions:

• chrX-154532662-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.1192G>A​(p.Glu398Lys) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.67

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, 0.987
• PP5: Variant X-154532662-C-T is Pathogenic according to our data. Variant chrX-154532662-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 804134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532662-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.1192G>A	p.Glu398Lys	missense_variant	10/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1282G>A	p.Glu428Lys	missense_variant	10/13		NP_000393.4
G6PD	NM_001042351.3	c.1192G>A	p.Glu398Lys	missense_variant	10/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1192G>A	p.Glu398Lys	missense_variant	10/13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.1192G>A(p.Glu398Lys) in the G6PD gene has been reported previously in individual(s) with G6PD deficiency (Tong Y, et al., 2020). This variant is located in a mutational hot spot. A different amino acid change [c.1193A>G (p.Glu398Gly)] at the same position has been submitted to ClinVar as likely pathogenic. This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Glutamic acid at position 398 is changed to a Lysine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
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). In one family, heizygous brothers both have deficiency CNSHA, and mother is heterozygous (PP1). Undetectable activity in red blood cells (PS3). Within dimer interface (PM1). Not found in gnomAD (PM2). Reported as pathogenic by Mendelics (PP5). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.6	H;H;H;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	.;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Pathogenic	0.0010	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.63
MutPred		0.95		Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.96
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: rs137852325; hg19: chrX-153760877; COSMIC: COSV100855133; COSMIC: COSV100855133;