rs144832032
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate
The NM_000071.3(CBS):c.404C>T(p.Thr135Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. T135?) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000071.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.404C>T | p.Thr135Met | missense_variant | 5/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.404C>T | p.Thr135Met | missense_variant | 5/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000801 AC: 8AN: 99908Hom.: 1 Cov.: 14
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250664Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135632
GnomAD4 exome AF: 0.0000301 AC: 30AN: 997794Hom.: 1 Cov.: 15 AF XY: 0.0000295 AC XY: 15AN XY: 508924
GnomAD4 genome AF: 0.0000801 AC: 8AN: 99908Hom.: 1 Cov.: 14 AF XY: 0.0000620 AC XY: 3AN XY: 48364
ClinVar
Submissions by phenotype
Classic homocystinuria Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 15, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 08, 2022 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 18, 2023 | The p.T135M variant (also known as c.404C>T), located in coding exon 3 of the CBS gene, results from a C to T substitution at nucleotide position 404. The threonine at codon 135 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 26, 2022 | BP4 - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 135 of the CBS protein (p.Thr135Met). This variant is present in population databases (rs144832032, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 471364). 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 not expected to disrupt CBS protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at