rs1000697114

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP3_StrongPP5_Moderate

The NM_000071.3(CBS):​c.766G>A​(p.Gly256Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G256V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 3)

Consequence

CBS
NM_000071.3 missense

Scores

11
7
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.85
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000071.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-43063961-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2505463.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.997
PP5
Variant 21-43063962-C-T is Pathogenic according to our data. Variant chr21-43063962-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 573223.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CBSNM_000071.3 linkuse as main transcriptc.766G>A p.Gly256Ser missense_variant 9/17 ENST00000398165.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CBSENST00000398165.8 linkuse as main transcriptc.766G>A p.Gly256Ser missense_variant 9/171 NM_000071.3 P1P35520-1

Frequencies

GnomAD3 genomes
Cov.:
3
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
3

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 15, 2023For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt CBS protein function. ClinVar contains an entry for this variant (Variation ID: 573223). This missense change has been observed in individual(s) with clinical features of CBS-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 256 of the CBS protein (p.Gly256Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;D;D;D
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
.;.;.;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
1.0
D;D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
3.0
M;M;M;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.8
D;D;D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.98
MutPred
0.98
Gain of glycosylation at G256 (P = 0.1447);Gain of glycosylation at G256 (P = 0.1447);Gain of glycosylation at G256 (P = 0.1447);Gain of glycosylation at G256 (P = 0.1447);
MVP
0.95
MPC
1.1
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.97
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs1000697114; hg19: chr21-44484072; API