rs137852313

chrX-154535187-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001360016.2(G6PD):c.466G>A(p.Glu156Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000868 in 1,209,283 control chromosomes in the GnomAD database, including 2 homozygotes. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000081 (2 hom. 29 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1 O:1
• Conservation: PhyloP100: 0.964

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001360016.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.060296565).
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.466G>A	p.Glu156Lys	missense_variant	5/13	ENST00000393562.10
G6PD	NM_000402.4	c.556G>A	p.Glu186Lys	missense_variant	5/13
G6PD	NM_001042351.3	c.466G>A	p.Glu156Lys	missense_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.466G>A	p.Glu156Lys	missense_variant	5/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 16 AN: 111791 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 33985

Gnomad AFR AF: 0.000390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.000273 AC: 50 AN: 183269 Hom.: 1 AF XY: 0.000266 AC XY: 18 AN XY: 67741

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000419

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000811 AC: 89 AN: 1097438 Hom.: 2 Cov.: 31 AF XY: 0.0000799 AC XY: 29 AN XY: 363082

Gnomad4 AFR exome AF: 0.000607

Gnomad4 AMR exome AF: 0.000966

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000444

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.0000652

GnomAD4 genome AF: 0.000143 AC: 16 AN: 111845 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 34049

Gnomad4 AFR AF: 0.000389

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000313 AC: 38

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in hemizygotes with G6PD deficiency (PP4). Decreased activity in red blood cells of hemizygotes (21-25%) (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1). -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 28, 2024

Variant summary: G6PD c.556G>A (p.Glu186Lys) results in a conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 183269 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00027 vs 0.29), allowing no conclusion about variant significance. c.556G>A has been reported in the literature in individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency. These report(s) do not provide unequivocal conclusions about association of the variant with Glucose 6 Phosphate Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 10364). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 24, 2022

- -

G6PD ILESHA 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	Benign	0.097
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	16
Dann	Benign	0.67
DEOGEN2	Uncertain	0.70	D;D;D;.;D;.;D
FATHMM_MKL	Benign	0.027	N
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.060	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.49	N;N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.44	T
Sift4G	Benign	1.0	T;.;T;T;.;.;.
Polyphen		0.0050	B;B;B;.;.;.;.
Vest4		0.20
MVP		0.99
MPC		0.20
ClinPred		0.0018	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.56

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: rs137852313; hg19: chrX-153763402;