20-34932027-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000178.4(GSS):c.941C>T(p.Pro314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000569 in 1,614,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000178.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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GSS | NM_000178.4 | c.941C>T | p.Pro314Leu | missense_variant | Exon 10 of 13 | ENST00000651619.1 | NP_000169.1 | |
GSS | NM_001322494.1 | c.941C>T | p.Pro314Leu | missense_variant | Exon 10 of 13 | NP_001309423.1 | ||
GSS | NM_001322495.1 | c.941C>T | p.Pro314Leu | missense_variant | Exon 10 of 13 | NP_001309424.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00269 AC: 410AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000824 AC: 207AN: 251350Hom.: 1 AF XY: 0.000699 AC XY: 95AN XY: 135904
GnomAD4 exome AF: 0.000348 AC: 509AN: 1461862Hom.: 2 Cov.: 32 AF XY: 0.000322 AC XY: 234AN XY: 727232
GnomAD4 genome AF: 0.00269 AC: 409AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.00254 AC XY: 189AN XY: 74474
ClinVar
Submissions by phenotype
Inherited glutathione synthetase deficiency Uncertain:1Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
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not specified Benign:2
Variant summary: GSS c.941C>T (p.Pro314Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 251350 control chromosomes, including one homozygote in the general population (gnomAD). The variant occurs predominantly at a frequency of 0.0094 within the African or African-American subpopulation in the gnomAD database, which is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in GSS causing Glutathione Synthetase Deficiency phenotype (0.003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.941C>T has been reported in the literature in one individual affected with Glutathione Synthetase Deficiency (Shi_1996), occuring in cis with a second pathogenic variant (GSS c.1139_1144del, p.Val380_Gln381del), providing supporting evidence for a benign role. Experimental evidence evaluating protein function demonstrated the variant does not impact enzyme function in vitro (Njallson_2004) or in a yeast complementation assay (Shi_1996). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance and three as benign. Based on the evidence outlined above, the variant was classified as benign. -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Glutathione synthetase deficiency with 5-oxoprolinuria Benign:1
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not provided Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at