X-154532389-C-T

Position:

• chrX-154532389-C-T

Variant summary

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

The ENST00000393562.10(G6PD):​c.1361G>A​(p.Arg454His) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,097,547 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R454C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: G6PD ENST00000393562.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 5.68

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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in ENST00000393562.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532390-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 93493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-154532389-C-T is Pathogenic according to our data. Variant chrX-154532389-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532389-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.1361G>A	p.Arg454His	missense_variant	11/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1451G>A	p.Arg484His	missense_variant	11/13		NP_000393.4
G6PD	NM_001042351.3	c.1361G>A	p.Arg454His	missense_variant	11/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1361G>A	p.Arg454His	missense_variant	11/13	1	NM_001360016.2	ENSP00000377192	P4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182012 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67092

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097547 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 363103

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: 0.0000249

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency and jaundice, favism, and CNSHA (PS4_M, PP4). Decreased activity in red blood cells and when expressed in E. coli (PS3). Affects same amino acid as pathogenic 454R>C (ClinVar ID 93493) (PM5). Below expected carrier frequency in gnomAD (PM2). Post_P 0.997 (odds of pathogenicity 3158, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 05, 2022	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg454 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10221015, 12497642, 16088936, 22293322, 26823837). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects G6PD function (PMID: 16088936). 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. ClinVar contains an entry for this variant (Variation ID: 10379). This missense change has been observed in individual(s) with favism (PMID: 2393028, 12497642). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 454 of the G6PD protein (p.Arg454His). -

G6PD ANDALUS Other:1

other, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.0	.;.;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.83
MutPred		0.96		Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);.;
MVP		1.0
MPC		2.3
ClinPred		0.94	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.97

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: rs137852324; hg19: chrX-153760604;