chr21-43056876-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_StrongBP6BP7BS2_Supporting

The NM_000071.3(CBS):c.1479G>A(p.Thr493Thr) 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T493T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00035 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -2.33

Publications

1 publications found

Variant links:

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

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.012).

BP6

Variant 21-43056876-C-T is Benign according to our data. Variant chr21-43056876-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212834.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP7

Synonymous conserved (PhyloP=-2.33 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.1479G>A	p.Thr493Thr	synonymous_variant	Exon 16 of 17	ENST00000398165.8	NP_000062.1	P35520-1Q9NTF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.1479G>A	p.Thr493Thr	synonymous_variant	Exon 16 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

2474

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000368

AC:

AN:

160528

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.000220

Gnomad AMR exome

AF:

0.000239

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000858

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000676

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000346

AC:

AN:

162074

Hom.:

Cov.:

AF XY:

0.000319

AC XY:

AN XY:

87886

show subpopulations

African (AFR)

AF:

0.000422

AC:

AN:

4734

American (AMR)

AF:

0.000157

AC:

AN:

12772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3714

East Asian (EAS)

AF:

0.00

AC:

AN:

10710

South Asian (SAS)

AF:

0.000155

AC:

AN:

32332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6944

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

638

European-Non Finnish (NFE)

AF:

0.000524

AC:

AN:

82044

Other (OTH)

AF:

0.000366

AC:

AN:

8186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

2482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

1250

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

1090

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

184

South Asian (SAS)

AF:

0.00

AC:

AN:

150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

734

Other (OTH)

AF:

0.00

AC:

AN:

Alfa

AF:

0.000238

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CBS: BP4, BP7 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Classic homocystinuria

Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature. This variant may be present in the general population, but population data for this variant is unreliable due to the presence of a highly homologous pseudogene. This variant is present in ClinVar, with classifications ranging from likely benign to variant of uncertain significance (Variation ID: 212834). This is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. Splice prediction tools suggest that this variant may affect splicing, although further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. However, we cannot rule out the possibility that this variant is present in the pseudogene rather than in the real protein-coding gene. -

not specified

Benign:1

Aug 18, 2014

GeneDx

Significance: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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Sep 19, 2016

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 27, 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

-0.47

CADD

Benign

0.076

(source)

DANN

Benign

0.65

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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chr21-43056876-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over