rs73906420

Positions:

chr21-43065480-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000071.3(CBS):c.573G>A(p.Thr191=) 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 (★★).

Frequency

Genomes: 𝑓 0.0061 ( 5 hom., cov: 4)

Exomes 𝑓: 0.0088 ( 802 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -6.46

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 21-43065480-C-T is Benign according to our data. Variant chr21-43065480-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43065480-C-T is described in Lovd as [Benign]. Variant chr21-43065480-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-6.45 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00881 (3668/416138) while in subpopulation MID AF= 0.0402 (73/1814). AF 95% confidence interval is 0.0328. There are 802 homozygotes in gnomad4_exome. There are 1959 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 802 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.573G>A	p.Thr191=	synonymous_variant	7/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.573G>A	p.Thr191=	synonymous_variant	7/17	1	NM_000071.3	P1	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

108

AN:

17188

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.0381

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00465

Gnomad FIN

AF:

0.000638

Gnomad MID

AF:

0.0652

Gnomad NFE

AF:

0.00678

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00585

AC:

1457

AN:

248930

Hom.:

AF XY:

0.00622

AC XY:

839

AN XY:

134806

show subpopulations

Gnomad AFR exome

AF:

0.00541

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00749

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00617

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.00881

AC:

3668

AN:

416138

Hom.:

802

Cov.:

AF XY:

0.00890

AC XY:

1959

AN XY:

220148

show subpopulations

Gnomad4 AFR exome

AF:

0.00724

Gnomad4 AMR exome

AF:

0.00409

Gnomad4 ASJ exome

AF:

0.0396

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0110

Gnomad4 FIN exome

AF:

0.000380

Gnomad4 NFE exome

AF:

0.00905

Gnomad4 OTH exome

AF:

0.0100

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00614

AC:

106

AN:

17274

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

AN XY:

8070

show subpopulations

Gnomad4 AFR

AF:

0.00614

Gnomad4 AMR

AF:

0.00448

Gnomad4 ASJ

AF:

0.0381

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00459

Gnomad4 FIN

AF:

0.000638

Gnomad4 NFE

AF:

0.00678

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00733

Hom.:

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00829

EpiControl

AF:

0.00842

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2020	Variant summary: CBS c.573G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0059 in 248930 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CBS causing Homocystinuria phenotype (0.003), strongly suggesting that the variant is benign. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Thr191Thr in exon 7 of CBS: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.7% (64/8600) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs73906420). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CBS: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Classic homocystinuria

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 26, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 03, 2014

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.56

DANN

Benign

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over