rs1801181

Positions:

• chr21-43060506-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000071.3(CBS):​c.1080C>T​(p.Ala360Ala) 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (0 hom., cov: 0)
  • Exomes 𝑓: 0.38 (3618 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: -2.38

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 21-43060506-G-A is Benign according to our data. Variant chr21-43060506-G-A is described in ClinVar as [Benign]. Clinvar id is 92424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43060506-G-A is described in Lovd as [Benign]. Variant chr21-43060506-G-A is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.1080C>T	p.Ala360Ala	synonymous_variant	12/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1080C>T	p.Ala360Ala	synonymous_variant	12/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 14 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00

Gnomad SAS AF: 0.167

Gnomad NFE AF: 0.00

GnomAD3 exomes AF: 0.334 AC: 80942 AN: 242274 Hom.: 15525 AF XY: 0.344 AC XY: 45498 AN XY: 132442

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.614

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.345

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.382 AC: 15726 AN: 41214 Hom.: 3618 Cov.: 0 AF XY: 0.382 AC XY: 8379 AN XY: 21958

Gnomad4 AFR exome AF: 0.0571

Gnomad4 AMR exome AF: 0.212

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.609

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.423

Gnomad4 OTH exome AF: 0.419

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0833 AC: 1 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.336 Hom.: 2975

Asia WGS AF: 0.419 AC: 1458 AN: 3478

EpiCase AF: 0.355

EpiControl AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 62.069% in ExAC) based on the frequency threshold of 1.432% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ala360Ala in exon 12 of CBS: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 35.9% (3087/8594) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1801181). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.12
DANN	Benign	0.59

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: rs1801181; hg19: chr21-44480616; COSMIC: COSV61441401; COSMIC: COSV61441401;