rs1057518975

Positions:

• chrX-154532758-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001360016.2(G6PD):​c.1096A>G​(p.Lys366Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K366K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.51

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.1096A>G	p.Lys366Glu	missense_variant	10/13	ENST00000393562.10
G6PD	NM_000402.4	c.1186A>G	p.Lys396Glu	missense_variant	10/13
G6PD	NM_001042351.3	c.1096A>G	p.Lys366Glu	missense_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.1096A>G	p.Lys366Glu	missense_variant	10/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemolytic anemia;C5235039:Decreased glucosephosphate isomerase level Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 14, 2014

- -

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

Uncertain significance, criteria provided, single submitter

curation

Dunham Lab, University of Washington

Aug 12, 2022

Variant found in hemizygote with deficiency (PP4). Not found in gnomAD (PM2). Post_P 0.500 (odds of pathogenicity 9.01, Prior_P 0.1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;.
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.0040	D;.;D;D
Polyphen		0.73	P;P;P;.
Vest4		0.83
MutPred		0.82		Loss of ubiquitination at K366 (P = 0.027);Loss of ubiquitination at K366 (P = 0.027);Loss of ubiquitination at K366 (P = 0.027);.;
MVP		1.0
MPC		1.5
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.99
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: rs1057518975; hg19: chrX-153760973;