rs140979604
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_025265.4(TSEN2):āc.872A>Gā(p.Tyr291Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,612,184 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y291H) has been classified as Uncertain significance.
Frequency
Consequence
NM_025265.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSEN2 | NM_025265.4 | c.872A>G | p.Tyr291Cys | missense_variant | 6/12 | ENST00000284995.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSEN2 | ENST00000284995.11 | c.872A>G | p.Tyr291Cys | missense_variant | 6/12 | 1 | NM_025265.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000311 AC: 78AN: 251194Hom.: 2 AF XY: 0.000243 AC XY: 33AN XY: 135774
GnomAD4 exome AF: 0.000142 AC: 207AN: 1459904Hom.: 3 Cov.: 28 AF XY: 0.000140 AC XY: 102AN XY: 726420
GnomAD4 genome AF: 0.000197 AC: 30AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74472
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 291 of the TSEN2 protein (p.Tyr291Cys). This variant is present in population databases (rs140979604, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TSEN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 212445). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSEN2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 14, 2015 | - - |
Pontoneocerebellar hypoplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at