rs1555874223

Positions:

• chr21-43063061-G-GGATCCACCCCAATGATCTGCAGAGGGCGCGGCTTCAGGGCTCAAGCCCAGCAAAAGCCCCACCTGGAT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PVS1 BP6_Moderate

The NM_000071.3(CBS):​c.845_846insATCCAGGTGGGGCTTTTGCTGGGCTTGAGCCCTGAAGCCGCGCCCTCTGCAGATCATTGGGGTGGATC​(p.Glu283fs) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 frameshift, stop_gained
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 8.70

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 21-43063061-G-GGATCCACCCCAATGATCTGCAGAGGGCGCGGCTTCAGGGCTCAAGCCCAGCAAAAGCCCCACCTGGAT is Benign according to our data. Variant chr21-43063061-G-GGATCCACCCCAATGATCTGCAGAGGGCGCGGCTTCAGGGCTCAAGCCCAGCAAAAGCCCCACCTGGAT is described in ClinVar as [Likely_benign]. Clinvar id is 264368.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.845_846insATCCAGGTGGGGCTTTTGCTGGGCTTGAGCCCTGAAGCCGCGCCCTCTGCAGATCATTGGGGTGGATC	p.Glu283fs	frameshift_variant, stop_gained	10/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.845_846insATCCAGGTGGGGCTTTTGCTGGGCTTGAGCCCTGAAGCCGCGCCCTCTGCAGATCATTGGGGTGGATC	p.Glu283fs	frameshift_variant, stop_gained	10/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Classic homocystinuria Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555874223; hg19: chr21-44483171;