rs137852343

chrX-154534465-A-G

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):c.517T>C(p.Phe173Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,041 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. F173F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.04

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 24 ACMG points.

• PS1: Transcript NM_001360016.2 (G6PD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1722656
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-154534465-A-G is Pathogenic according to our data. Variant chrX-154534465-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534465-A-G is described in Lovd as [Pathogenic]. Variant chrX-154534465-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.517T>C	p.Phe173Leu	missense_variant	6/13	ENST00000393562.10
G6PD	NM_000402.4	c.607T>C	p.Phe203Leu	missense_variant	6/13
G6PD	NM_001042351.3	c.517T>C	p.Phe173Leu	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.517T>C	p.Phe173Leu	missense_variant	6/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 182837 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67403

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

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: 9.11e-7 AC: 1 AN: 1098041 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363425

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: 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:2

Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency, some with jaundice (PS4_M, PP4). Decreased activity in red blood cells (5-33%) (PS3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by Invitae (PP5). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 11, 2022	For these reasons, this variant has been classified as 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. ClinVar contains an entry for this variant (Variation ID: 10407). This variant is also known as G6PD NanKang. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 16329560, 20582980, 30045279). This variant is present in population databases (rs137852343, gnomAD 0.02%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the G6PD protein (p.Phe173Leu). -

Malaria, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 26, 2023

- -

G6PD NANKANG Other:1

other, no assertion criteria provided

literature only

OMIM

Apr 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.76
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.2	M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
Sift4G	Pathogenic	0.0	D;.;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.88
MutPred		0.94		Gain of catalytic residue at F173 (P = 0.0069);Gain of catalytic residue at F173 (P = 0.0069);Gain of catalytic residue at F173 (P = 0.0069);Gain of catalytic residue at F173 (P = 0.0069);.;.;Gain of catalytic residue at F173 (P = 0.0069);
MVP		1.0
MPC		0.77
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.98
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: rs137852343; hg19: chrX-153762680;