rs1801181
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000071.3(CBS):c.1080C>T(p.Ala360=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.083 ( 0 hom., cov: 0)
Exomes 𝑓: 0.38 ( 3618 hom. )
Failed GnomAD Quality Control
Consequence
CBS
NM_000071.3 synonymous
NM_000071.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.38
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
?
Variant 21-43060506-G-A is Benign according to our data. Variant chr21-43060506-G-A is described in ClinVar as [Benign]. Clinvar id is 92424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43060506-G-A is described in Lovd as [Benign]. Variant chr21-43060506-G-A is described in Lovd as [Pathogenic].
BP7
?
Synonymous conserved (PhyloP=-2.38 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.1080C>T | p.Ala360= | synonymous_variant | 12/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.1080C>T | p.Ala360= | synonymous_variant | 12/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 14Hom.: 0 Cov.: 0 FAILED QC
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GnomAD3 exomes AF: 0.334 AC: 80942AN: 242274Hom.: 15525 AF XY: 0.344 AC XY: 45498AN XY: 132442
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.382 AC: 15726AN: 41214Hom.: 3618 Cov.: 0 AF XY: 0.382 AC XY: 8379AN XY: 21958
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0833 AC: 1AN: 12Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 4
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Benign:6
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 14, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 28, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Sep 23, 2015 | - - |
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 12, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 04, 2013 | Ala360Ala in exon 12 of CBS: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 35.9% (3087/8594) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1801181). - |
not provided Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 62.069% in ExAC) based on the frequency threshold of 1.432% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2018 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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