rs748695461

Variant names:

• chr21-43072174-TG-T
• rs748695461
• NM_000071.3:c.19delC

Your query was ambiguous. Multiple possible variants found:

• chr21-43072174-TG-T
• chr21-43072174-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000071.3(CBS):​c.19delC​(p.Gln7ArgfsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.0790

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 172 pathogenic variants in the truncated region.
• PP5: Variant 21-43072174-TG-T is Pathogenic according to our data. Variant chr21-43072174-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 859549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43072174-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.19delC	p.Gln7ArgfsTer75	frameshift_variant	Exon 3 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.19delC	p.Gln7ArgfsTer75	frameshift_variant	Exon 3 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:1

Jan 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

May 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 859549). This premature translational stop signal has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 25218699). This variant is present in population databases (rs748695461, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Gln7Argfs*75) in the CBS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CBS are known to be pathogenic (PMID: 10338090, 12124992). -

Computational scores

Source: dbNSFP v4.3

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: rs748695461; hg19: chr21-44492284;