rs773734233

Positions:

chr21-43065239-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.700G>A(p.Asp234Asn) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D234D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000086 ( 1 hom., cov: 15)

Exomes 𝑓: 0.000019 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.65

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000071.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 21-43065239-C-T is Pathogenic according to our data. Variant chr21-43065239-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 212852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43065239-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.700G>A	p.Asp234Asn	missense_variant	8/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.700G>A	p.Asp234Asn	missense_variant	8/17	1	NM_000071.3	P1	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

127908

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000389

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:

0.00176

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251422

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000193

AC:

AN:

1293816

Hom.:

Cov.:

AF XY:

0.0000186

AC XY:

AN XY:

644588

show subpopulations

Gnomad4 AFR exome

AF:

0.0000946

Gnomad4 AMR exome

AF:

0.0000465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000517

Gnomad4 OTH exome

AF:

0.0000368

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000860

AC:

AN:

127908

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

62044

show subpopulations

Gnomad4 AFR

AF:

0.0000846

Gnomad4 AMR

AF:

0.000389

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00176

Bravo

AF:

0.0000793

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 10, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that D234N expression in E. coli cells reduces CBS enzyme activity and D234N expression in Hek 293 cells leads to less soluble and fewer properly assembled subunits, suggesting D234N may lead to an unstable protein that is less able to assemble into a functional enzyme (Casique et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10338090, 14972327, 22267502, 20303981, 19914636, 16786517, 23981774) -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 234 of the CBS protein (p.Asp234Asn). This variant is present in population databases (rs773734233, gnomAD 0.006%). This missense change has been observed in individual(s) with homocystinuria (PMID: 14972327, 16786517; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212852). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502, 23981774). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 26, 2016

Variant summary: The CBS c.700G>A (p.Asp234Asn) variant causes a missense change located in the CBS N-terminal catalytic domain at a position that is conserved across species (De Luca et al., 2004). This involves a conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "damaging" outcome, which is further supported with functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121342 (1/60671), which does not exceed the estimated maximal expected allele frequency for a pathogenic CBS variant of 1/328 (0.0030414). The variant of interest has been reported in multiple affected individuals via publications including 2 homozygous individuals. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.0027

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

.;.;.;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.022

D;D;D;D

Sift4G

Uncertain

0.031

D;D;D;D

Polyphen

0.99

D;D;D;D

Vest4

0.89

MutPred

0.79

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.94

MPC

1.1

ClinPred

0.88

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.85

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