rs141717913

Variant names:

• chr21-43058920-G-A
• rs141717913
• NM_000071.3:c.1272C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43058920-G-A
• chr21-43058920-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_000071.3(CBS):​c.1272C>T​(p.Thr424Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T424T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -7.83
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• classic homocystinuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.127).
• BP6: Variant 21-43058920-G-A is Benign according to our data. Variant chr21-43058920-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 236934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.83 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1272C>T	p.Thr424Thr	synonymous_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.1272C>T	p.Thr424Thr	synonymous_variant	Exon 14 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.000162 AC: 31 AN: 191612 AF XY: 0.000126

Gnomad AFR exome AF: 0.0000877

Gnomad AMR exome AF: 0.000604

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000849

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000112 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 14, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 04, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 19, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0050
DANN	Benign	0.59
PhyloP100		-7.8
PromoterAI		0.0021	Neutral

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

Other links and lift over

dbSNP: rs141717913; hg19: chr21-44479030;