chrX-154532269-C-T

Position:

• chrX-154532269-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM5 PP5_Moderate BS2_Supporting

The ENST00000393562.10(G6PD):​c.1376G>A​(p.Arg459His) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,097,707 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R459G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: G6PD ENST00000393562.10 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 Uncertain_significance. Variant got 5 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, 1 uncertain in ENST00000393562.10
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532270-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1722634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant X-154532269-C-T is Pathogenic according to our data. Variant chrX-154532269-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1485870.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1376G>A	p.Arg459His	missense_variant	12/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1466G>A	p.Arg489His	missense_variant	12/13		NP_000393.4
G6PD	NM_001042351.3	c.1376G>A	p.Arg459His	missense_variant	12/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1376G>A	p.Arg459His	missense_variant	12/13	1	NM_001360016.2	ENSP00000377192	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181938 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000528

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097707 Hom.: 0 Cov.: 37 AF XY: 0.0000110 AC XY: 4 AN XY: 363133

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000831

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2022

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. This variant disrupts the p.Arg459 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1562739, 2263506, 6714986, 8537082, 10643148, 11499668, 17726510, 20203002, 21446359, 25541721, 25775246, 26823837). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1485870). This variant has not been reported in the literature in individuals affected with G6PD-related conditions. This variant is present in population databases (rs72554665, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 459 of the G6PD protein (p.Arg459His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;D;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.9	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	.;.;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.063	.;.;T;T
Sift4G	Benign	0.065	T;.;T;T
Polyphen		0.041	B;B;B;.
Vest4		0.54
MutPred		0.65		Gain of disorder (P = 0.1343);Gain of disorder (P = 0.1343);Gain of disorder (P = 0.1343);.;
MVP		1.0
MPC		2.1
ClinPred		0.48	T
GERP RS		5.6
Varity_R		0.52
gMVP		0.90

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: rs72554665; hg19: chrX-153760484; COSMIC: COSV104682734; COSMIC: COSV104682734;