rs137852319

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_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

Scores

12
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 0.504
Variant links:
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]

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ACMG classification

Classification made for transcript

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
G6PDNM_001360016.2 linkuse as main transcriptc.648T>G p.Phe216Leu missense_variant 7/13 ENST00000393562.10
G6PDNM_000402.4 linkuse as main transcriptc.738T>G p.Phe246Leu missense_variant 7/13
G6PDNM_001042351.3 linkuse as main transcriptc.648T>G p.Phe216Leu missense_variant 7/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
G6PDENST00000393562.10 linkuse as main transcriptc.648T>G p.Phe216Leu missense_variant 7/131 NM_001360016.2 P4P11413-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submittercurationDunham Lab, University of WashingtonAug 12, 2022Variant 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 providedliterature onlyOMIMApr 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
LIST_S2
Pathogenic
0.98
.;.;D;D;D;D;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
PROVEAN
Pathogenic
-5.7
.;.;D;D;D;D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0010
.;.;D;D;D;D;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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852319; hg19: chrX-153762372; API