rs34193178

Positions:

• chrX-154532945-C-G
• chrX-154532945-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS2_Supporting

The NM_001360016.2(G6PD):​c.1048G>C​(p.Asp350His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,210,701 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 63 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 32 hem., cov: 24)
  • Exomes 𝑓: 0.00012 (0 hom. 31 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 7.29

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 -1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001360016.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.18980572).
• BS2: High Hemizygotes in GnomAd4 at 32 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	UniProt
G6PD	NM_001360016.2	c.1048G>C	p.Asp350His	missense_variant	9/13	ENST00000393562.10
G6PD	NM_000402.4	c.1138G>C	p.Asp380His	missense_variant	9/13
G6PD	NM_001042351.3	c.1048G>C	p.Asp350His	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1048G>C	p.Asp350His	missense_variant	9/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 116 AN: 112465 Hom.: 0 Cov.: 24 AF XY: 0.000924 AC XY: 32 AN XY: 34621

Gnomad AFR AF: 0.00358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000465

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000399 AC: 73 AN: 182804 Hom.: 0 AF XY: 0.000252 AC XY: 17 AN XY: 67436

Gnomad AFR exome AF: 0.00403

Gnomad AMR exome AF: 0.000620

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000124 AC: 136 AN: 1098182 Hom.: 0 Cov.: 33 AF XY: 0.0000853 AC XY: 31 AN XY: 363554

Gnomad4 AFR exome AF: 0.00352

Gnomad4 AMR exome AF: 0.000682

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.000390

GnomAD4 genome AF: 0.00103 AC: 116 AN: 112519 Hom.: 0 Cov.: 24 AF XY: 0.000923 AC XY: 32 AN XY: 34685

Gnomad4 AFR AF: 0.00358

Gnomad4 AMR AF: 0.000465

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000160 Hom.: 3

Bravo AF: 0.00123

ESP6500AA AF: 0.00235 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000338 AC: 41

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:2

Pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	G6PD: BS2 -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 19, 2023	- -

G6PD deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Dec 12, 2022

Variant summary: G6PD c.1138G>C (p.Asp380His) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, C-terminal domain (IPR022675) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 204594 control chromosomes, including 23 hemizygotes (gnomAD). c.1138G>C, also known as the "Mira d'Aire" variant, has been reported in the literature in individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Bulliamy_1997, Manco_2007, Powers_2018). These reports 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. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.65
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;D;.
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
Sift4G	Uncertain	0.019	D;.;D;D
Polyphen		0.95	P;P;P;.
Vest4		0.71
MVP		1.0
MPC		2.2
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.79
gMVP		0.96

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: rs34193178; hg19: chrX-153761160;