rs769541394
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000071.3(CBS):c.953C>T(p.Thr318Met) variant causes a missense, splice region change. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T318T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 0)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CBS
NM_000071.3 missense, splice_region
NM_000071.3 missense, splice_region
Scores
2
9
8
Splicing: ADA: 0.001946
2
Clinical Significance
Conservation
PhyloP100: 3.81
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 Uncertain_significance. Variant got 2 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000071.3
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.953C>T | p.Thr318Met | missense_variant, splice_region_variant | 10/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.953C>T | p.Thr318Met | missense_variant, splice_region_variant | 10/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 0
GnomAD3 genomes
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0
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251150Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135818
GnomAD3 exomes
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GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 18Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 12
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
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GnomAD4 genome Cov.: 0
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 12, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 29, 2018 | The CBS c.953C>T; p.Thr318Met variant (rs769541394), to our knowledge, is not reported in the medical literature in association with a CBS related disorder, but it is reported as a variant of uncertain significance in ClinVar (Variation ID: 405378). This variant is found in the general population with an overall allele frequency of 0.0045% (11/245,976 alleles) in the Genome Aggregation Database. The threonine at codon 318 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the c.953C>T variant is uncertain at this time. - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 318 of the CBS protein (p.Thr318Met). This variant is present in population databases (rs769541394, gnomAD 0.02%). 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: 405378). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Loss of phosphorylation at T318 (P = 0.0217);Loss of phosphorylation at T318 (P = 0.0217);Loss of phosphorylation at T318 (P = 0.0217);Loss of phosphorylation at T318 (P = 0.0217);
MVP
MPC
0.41
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at