21-43058919-C-G

Variant names:

• chr21-43058919-C-G
• rs138211175
• NM_000071.3:c.1273G>C

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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]

ACMG classification

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	c.1273G>C	p.Val425Leu	missense_variant	Exon 14 of 17	ENST00000398165.8	NP_000062.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000522 AC: 1 AN: 191582 Hom.: 0 AF XY: 0.00000973 AC XY: 1 AN XY: 102826

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.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00000904 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	17
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	D
LIST_S2	Uncertain	0.89	.;.;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.8	L;L;L;L
PrimateAI	Uncertain	0.55	T
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	T
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

Other links and lift over

dbSNP: rs138211175; hg19: chr21-44479029;