rs137852319

chrX-154534157-A-CchrX-154534157-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001360016.2(G6PD):c.648T>G(p.Phe216Leu) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F216F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.504

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 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-154534157-A-C is Pathogenic according to our data. Variant chrX-154534157-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10373.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154534157-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.648T>G	p.Phe216Leu	missense_variant	7/13	ENST00000393562.10
G6PD	NM_000402.4	c.738T>G	p.Phe246Leu	missense_variant	7/13
G6PD	NM_001042351.3	c.648T>G	p.Phe216Leu	missense_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.648T>G	p.Phe216Leu	missense_variant	7/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

curation

Dunham Lab, University of Washington

Aug 12, 2022

Variant found in hemizygote and maternal uncle, both with G6PD deficiency and CNSHA (PP1, PP4). Decreased activity in fibroblasts (1%) (PS3). Not found in gnomAD (PM2). Post_P 0.975 (odds of pathogenicity 350.3, Prior_P 0.1). -

G6PD HARILAOU 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	0.63	D
BayesDel_noAF	Pathogenic	0.67
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0020	D;.;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.85
MutPred		0.95		Loss of MoRF binding (P = 0.1204);Loss of MoRF binding (P = 0.1204);Loss of MoRF binding (P = 0.1204);Loss of MoRF binding (P = 0.1204);.;.;Loss of MoRF binding (P = 0.1204);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		0.57
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852319; hg19: chrX-153762372;