rs73906420

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.Thr191Thr) 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

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

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]

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 rank MANE Protein UniProt
CBSNM_000071.3 linkc.573G>A p.Thr191Thr synonymous_variant Exon 7 of 17 ENST00000398165.8 NP_000062.1 P35520-1Q9NTF0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBSENST00000398165.8 linkc.573G>A p.Thr191Thr synonymous_variant Exon 7 of 17 1 NM_000071.3 ENSP00000381231.4 P35520-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
108
AN:
17188
Hom.:
5
Cov.:
4
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.:
12
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.:
0
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.:
5
Cov.:
4
AF XY:
0.00657
AC XY:
53
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.:
5
Asia WGS
AF:
0.00318
AC:
11
AN:
3478
EpiCase
AF:
0.00829
EpiControl
AF:
0.00842

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 06, 2013
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. -

Feb 19, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 04, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 24, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Benign:4
Jan 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CBS: BP4, BP7 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Oct 07, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Classic homocystinuria Benign:2
Dec 03, 2019
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 26, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jul 03, 2014
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
Feb 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Connective tissue disorder Benign:1
Dec 06, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: 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
-0.53
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.

Other links and lift over

dbSNP: rs73906420; hg19: chr21-44485590; COSMIC: COSV61444351; COSMIC: COSV61444351; API