rs1057518975
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_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
NM_001360016.2 missense
Scores
8
4
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;.;D;D
Polyphen
P;P;P;.
Vest4
MutPred
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
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at