21-43060519-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000071.3(CBS):c.1067T>C(p.Val356Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000071.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD3 exomes AF: 0.00000419 AC: 1AN: 238714Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131000
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 43102Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 22962
GnomAD4 genome Cov.: 0
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: CBS c.1067T>C (p.Val356Ala) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238714 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1067T>C in individuals affected with Homocystinuria has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no impact on growth in a S. cerevisiae model (example, Dimster-Denk_2013, Kasak_2019). The following publications have been ascertained in the context of this evaluation (PMID: 23934999, 31301157). ClinVar contains an entry for this variant (Variation ID: 519591). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.V356A variant (also known as c.1067T>C), located in coding exon 10 of the CBS gene, results from a T to C substitution at nucleotide position 1067. The valine at codon 356 is replaced by alanine, an amino acid with similar properties. This variant was included in a study of CBS alterations' B6 cofactor sensitivity and was reported as having no significant differences versus wild-type in yeast culture growth rate at increasing pyridoxine concentrations (Dimster-Denk D et al. G3 (Bethesda), 2013 Oct;3:1619-28). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Classic homocystinuria Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at