X-154532625-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_001360016.2(G6PD):​c.1229G>A​(p.Gly410Asp) variant causes a missense change. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G410C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 24)

Consequence

G6PD
NM_001360016.2 missense

Scores

13
2
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 5.68
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 12 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_001360016.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-154532626-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant X-154532625-C-T is Pathogenic according to our data. Variant chrX-154532625-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10398.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154532625-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
G6PDNM_001360016.2 linkuse as main transcriptc.1229G>A p.Gly410Asp missense_variant 10/13 ENST00000393562.10
G6PDNM_000402.4 linkuse as main transcriptc.1319G>A p.Gly440Asp missense_variant 10/13
G6PDNM_001042351.3 linkuse as main transcriptc.1229G>A p.Gly410Asp missense_variant 10/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
G6PDENST00000393562.10 linkuse as main transcriptc.1229G>A p.Gly410Asp missense_variant 10/131 NM_001360016.2 P4P11413-1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2
Pathogenic, criteria provided, single submittercurationDunham Lab, University of WashingtonAug 12, 2022Variant found in unrelated hemizygotes with deficiency and CNSHA (PS4_M, PP4). Decreased activity in red blood cells (0-3%) (PS3). Within dimer interface (PM1). Not found in gnomAD (PM2). Post_P 0.997 (odds of pathogenicity 3158, Prior_P 0.1). -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 11, 2024- -
G6PD JAPAN Other:1
other, no assertion criteria providedliterature onlyOMIMOct 11, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.70
D
BayesDel_noAF
Pathogenic
0.77
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;D;.
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.84
.;.;T;T
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
3.8
H;H;H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-6.3
.;.;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
.;.;D;D
Sift4G
Pathogenic
0.0
D;.;D;D
Polyphen
1.0
D;D;D;.
Vest4
0.88
MutPred
0.94
Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);.;
MVP
1.0
MPC
2.3
ClinPred
1.0
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.99

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

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

Other links and lift over

dbSNP: rs137852336; hg19: chrX-153760840; COSMIC: COSV63704338; COSMIC: COSV63704338; API