12-7070184-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS1_Supporting
The NM_001734.5(C1S):c.1600C>T(p.Arg534Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,614,016 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R534Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001734.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
C1S | NM_001734.5 | c.1600C>T | p.Arg534Trp | missense_variant | Exon 12 of 12 | ENST00000360817.10 | NP_001725.1 | |
C1S | NM_201442.4 | c.1600C>T | p.Arg534Trp | missense_variant | Exon 12 of 12 | NP_958850.1 | ||
C1S | NM_001346850.2 | c.1099C>T | p.Arg367Trp | missense_variant | Exon 11 of 11 | NP_001333779.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251114Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135726
GnomAD4 exome AF: 0.000108 AC: 158AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 83AN XY: 727206
GnomAD4 genome AF: 0.000210 AC: 32AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:3
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 534 of the C1S protein (p.Arg534Trp). This variant is present in population databases (rs121909582, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with C1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 17068). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt C1S 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. -
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not specified Uncertain:1
Variant summary: C1S c.1600C>T (p.Arg534Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251114 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in C1S causing Complement component C1s deficiency, allowing no conclusion about variant significance. c.1600C>T has been reported in the literature in an individual affected with an ALPS-like phenotype without strong evidence of causality (Grossi_2021). This report does not provide unequivocal conclusions about association of the variant with Complement component C1s deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34573280). ClinVar contains an entry for this variant (Variation ID: 17068). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Complement component C1s deficiency;C4310681:Ehlers-Danlos syndrome, periodontal type 2 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at