rs147040567

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000071.3(CBS):c.856A>G(p.Ile286Val) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I286T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 4.09

Publications

5 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: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.

BP4

Computational evidence support a benign effect (MetaRNN=0.25584212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.856A>G	p.Ile286Val	missense_variant	Exon 10 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.856A>G	p.Ile286Val	missense_variant	Exon 10 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000110

AC:

AN:

236066

AF XY:

0.000141

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000484

Gnomad NFE exome

AF:

0.000206

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

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

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000347

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Uncertain:4

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 06, 2017

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing;provider interpretation

This 6 year old male with global developmental delays is a compound heterozygote for 2 VUSs in the CBS gene (p.Glu283Lys and p.Ile286Val). The p.Ile286Val variant is present in the gnomAD non-Finnish European population at a frequency of 0.02%. Computational models predict it to benign. He has normal stature (30%tile). Subsequent clinical testing showed normal plasma homocysteine and methionine levels. -

not provided

Uncertain:2

Feb 19, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

May 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I286V variant (also known as c.856A>G), located in coding exon 8 of the CBS gene, results from an A to G substitution at nucleotide position 856. The isoleucine at codon 286 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Uncertain:1

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 286 of the CBS protein (p.Ile286Val). This variant is present in population databases (rs147040567, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 212855). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.76

D;D;D;D

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

.;.;.;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Uncertain

-0.056

MutationAssessor

Benign

0.21

N;N;N;N

PhyloP100

4.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.65

N;N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.015

B;B;B;B

Vest4

0.39

MVP

0.49

MPC

0.30

ClinPred

0.049

GERP RS

2.0

Varity_R

0.25

gMVP

0.71

Mutation Taster

=61/39

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over