rs775793638
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001079866.2(BCS1L):c.413C>T(p.Thr138Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T138T) has been classified as Likely benign.
Frequency
Consequence
NM_001079866.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCS1L | NM_001079866.2 | c.413C>T | p.Thr138Met | missense_variant | 3/8 | ENST00000359273.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCS1L | ENST00000359273.8 | c.413C>T | p.Thr138Met | missense_variant | 3/8 | 1 | NM_001079866.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251480Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Pili torti-deafness syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 11, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 27, 2023 | Variant summary: BCS1L c.413C>T (p.Thr138Met) results in a non-conservative amino acid change located in the BCS1, N-terminal domain of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251480 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.413C>T has been reported in the literature in individuals affected with Renal Tubulopathies or hypotonia/Leigh syndrome (Braun_2016, Loiselet_2021, Hikmat_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26489029, 33511646, 34662929). Two ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
GRACILE syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 16, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | 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. 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 BCS1L protein function. ClinVar contains an entry for this variant (Variation ID: 551829). This missense change has been observed in individual(s) with BCS1L-related conditions (PMID: 26489029). This variant is present in population databases (rs775793638, gnomAD 0.007%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 138 of the BCS1L protein (p.Thr138Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at