rs748695461
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000071.3(CBS):c.19del(p.Gln7ArgfsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q7Q) 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: 0.0790
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]
Genome browser will be placed here
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 342 pathogenic variants in the truncated region.
PP5
?
Variant 21-43072174-TG-T is Pathogenic according to our data. Variant chr21-43072174-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 859549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43072174-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.19del | p.Gln7ArgfsTer75 | frameshift_variant | 3/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.19del | p.Gln7ArgfsTer75 | frameshift_variant | 3/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 0
GnomAD3 genomes
?
Cov.:
0
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
GnomAD4 genome ? Cov.: 0
GnomAD4 genome
?
Cov.:
0
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 06, 2023 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 19, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 859549). This premature translational stop signal has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 25218699). This variant is present in population databases (rs748695461, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln7Argfs*75) 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). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at