rs779250698
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000071.3(CBS):c.28del(p.Val10TrpfsTer72) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V10V) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 0)
Consequence
CBS
NM_000071.3 frameshift
NM_000071.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.10
Genes affected
CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 345 pathogenic variants in the truncated region.
PP5
?
Variant 21-43072165-AC-A is Pathogenic according to our data. Variant chr21-43072165-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43072165-AC-A is described in Lovd as [Pathogenic]. Variant chr21-43072165-AC-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.28del | p.Val10TrpfsTer72 | frameshift_variant | 3/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.28del | p.Val10TrpfsTer72 | frameshift_variant | 3/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 0
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GnomAD3 exomes AF: 0.00000819 AC: 2AN: 244068Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133376
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GnomAD4 exome Cov.: 0
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GnomAD4 genome ? Cov.: 0
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 15, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 07, 2016 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 281010). This variant is also known as c.28_29delG. This premature translational stop signal has been observed in individuals with homocystinuria (PMID: 11359213, 29352562). This variant is present in population databases (rs779250698, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Val10Trpfs*72) in the CBS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CBS are known to be pathogenic (PMID: 10338090, 12124992). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at