rs73906420
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000071.3(CBS):c.573G>A(p.Thr191Thr) 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 Likely benign (★★).
Frequency
Consequence
NM_000071.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 108AN: 17188Hom.: 5 Cov.: 4 FAILED QC
GnomAD3 exomes AF: 0.00585 AC: 1457AN: 248930Hom.: 12 AF XY: 0.00622 AC XY: 839AN XY: 134806
GnomAD4 exome AF: 0.00881 AC: 3668AN: 416138Hom.: 802 Cov.: 0 AF XY: 0.00890 AC XY: 1959AN XY: 220148
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00614 AC: 106AN: 17274Hom.: 5 Cov.: 4 AF XY: 0.00657 AC XY: 53AN XY: 8070
ClinVar
Submissions by phenotype
not specified Benign:6
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Thr191Thr in exon 7 of CBS: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.7% (64/8600) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs73906420). -
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Variant summary: CBS c.573G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0059 in 248930 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBS causing Homocystinuria phenotype (0.003), strongly suggesting that the variant is benign. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:4
CBS: BP4, BP7 -
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Classic homocystinuria Benign:2
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
This alteration is classified as likely 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
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Connective tissue disorder Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at