dbSNP rs138211175: CBS:p.Val425Leu (chr21-43058919-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000071.3(CBS):c.1273G>C(p.Val425Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

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]

CBS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain CBS (size 58) in uniprot entity CBS_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000071.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.1273G>C	p.Val425Leu	missense_variant	Exon 14 of 17	ENST00000398165.8	NP_000062.1	P35520-1Q9NTF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.1273G>C	p.Val425Leu	missense_variant	Exon 14 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000522

AC:

AN:

191582

Hom.:

AF XY:

0.00000973

AC XY:

AN XY:

102826

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000904

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Uncertain:1

Feb 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 425 of the CBS protein (p.Val425Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CBS-related conditions. 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 with a positive predictive value of 80%. 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.80

D;D;D;D

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.072

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

.;.;.;D

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.50

T;T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.8

L;L;L;L

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.26

T;T;T;T

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.0090

B;B;B;B

Vest4

0.33

MutPred

0.63

Loss of glycosylation at T424 (P = 0.1492);Loss of glycosylation at T424 (P = 0.1492);Loss of glycosylation at T424 (P = 0.1492);Loss of glycosylation at T424 (P = 0.1492);

MVP

0.77

MPC

0.36

ClinPred

0.35

GERP RS

4.7

Varity_R

0.56

gMVP

0.73

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over