21-43060519-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000071.3(CBS):​c.1067T>C​(p.Val356Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 0)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.24
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

PM1
In a helix (size 12) in uniprot entity CBS_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000071.3
BP4
Computational evidence support a benign effect (MetaRNN=0.20725018).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBSNM_000071.3 linkc.1067T>C p.Val356Ala missense_variant Exon 12 of 17 ENST00000398165.8 NP_000062.1 P35520-1Q9NTF0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBSENST00000398165.8 linkc.1067T>C p.Val356Ala missense_variant Exon 12 of 17 1 NM_000071.3 ENSP00000381231.4 P35520-1

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD3 exomes
AF:
0.00000419
AC:
1
AN:
238714
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131000
show subpopulations
Gnomad AFR exome
AF:
0.0000656
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
43102
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
22962
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
0
Asia WGS
AF:
0.00289
AC:
10
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 15, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CBS c.1067T>C (p.Val356Ala) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238714 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1067T>C in individuals affected with Homocystinuria has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no impact on growth in a S. cerevisiae model (example, Dimster-Denk_2013, Kasak_2019). The following publications have been ascertained in the context of this evaluation (PMID: 23934999, 31301157). ClinVar contains an entry for this variant (Variation ID: 519591). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Dec 21, 2016
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.V356A variant (also known as c.1067T>C), located in coding exon 10 of the CBS gene, results from a T to C substitution at nucleotide position 1067. The valine at codon 356 is replaced by alanine, an amino acid with similar properties. This variant was included in a study of CBS alterations' B6 cofactor sensitivity and was reported as having no significant differences versus wild-type in yeast culture growth rate at increasing pyridoxine concentrations (Dimster-Denk D et al. G3 (Bethesda), 2013 Oct;3:1619-28). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other 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. -

Classic homocystinuria Uncertain:1
Sep 16, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.094
BayesDel_addAF
Benign
-0.038
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
0.63
DANN
Benign
0.23
DEOGEN2
Uncertain
0.65
D;D;D;D
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.27
N
LIST_S2
Benign
0.76
.;.;.;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.21
T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-1.8
N;N;N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
0.45
N;N;N;N
REVEL
Uncertain
0.40
Sift
Benign
1.0
T;T;T;T
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.0
B;B;B;B
Vest4
0.29
MutPred
0.72
Gain of ubiquitination at K359 (P = 0.0501);Gain of ubiquitination at K359 (P = 0.0501);Gain of ubiquitination at K359 (P = 0.0501);Gain of ubiquitination at K359 (P = 0.0501);
MVP
0.31
MPC
0.42
ClinPred
0.018
T
GERP RS
-0.12
Varity_R
0.13
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs370163789; hg19: chr21-44480629; API