Variant chr21-43062368-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The ENST00000398165.8(CBS):c.982G>A(p.Asp328Asn) variant causes a missense change. In-silico tool predicts a pathogenic 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. D328D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
ENST00000398165.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 6.85

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000398165.8

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 21-43062368-C-T is Pathogenic according to our data. Variant chr21-43062368-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550653.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.982G>A	p.Asp328Asn	missense_variant	11/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.982G>A	p.Asp328Asn	missense_variant	11/17	1	NM_000071.3	ENSP00000381231	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250848

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135748

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 08, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 25, 2018	The CBS c.982G>A; p.Asp328Asn variant (rs758447354) has been described in the compound heterozygous state in one individual with homocystinuria due to cystathionine beta-synthase deficiency (Silao 2015) and is observed in the general population at a low overall frequency of 0.0008% (2/245840 alleles) in the Genome Aggregation Database. The aspartic acid at codon 328 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Silao C et al. Novel cystathionine beta-synthase gene mutations in a Filipino patient with classic homocystinuria. Pediatr Int. 2015 Oct;57(5):884-7. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25939784) -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 328 of the CBS protein (p.Asp328Asn). This variant is present in population databases (rs758447354, gnomAD 0.002%). This missense change has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 25939784, 33057012). ClinVar contains an entry for this variant (Variation ID: 550653). 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. For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 24, 2023

Variant summary: CBS c.982G>A (p.Asp328Asn) results in a conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250848 control chromosomes (gnomAD). c.982G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with classic homocystinuria (Silao_2015, Kaur_2020, Alsharhan_2021), and in one case with congenital ectopia lentis (Chen_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

CBS-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 07, 2024

The CBS c.982G>A variant is predicted to result in the amino acid substitution p.Asp328Asn. This variant has been reported in multiple individuals in both the compound heterozygous and homozygous state with classic homocystinuria (Silao et al 2015. PubMed ID: 25939784; Table 2, Kaur et al 2020. PubMed ID: 33057012; Table 3, Alsharhan et al 2021. PubMed ID: 34449519) and in an individual with congenital ectopia lentis (Table 3, Chen et al 2021. PubMed ID: 34818515). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

.;.;.;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;M;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.94

MutPred

0.82

Gain of ubiquitination at K325 (P = 0.1064);Gain of ubiquitination at K325 (P = 0.1064);Gain of ubiquitination at K325 (P = 0.1064);Gain of ubiquitination at K325 (P = 0.1064);

MVP

0.93

MPC

1.1

ClinPred

1.0

GERP RS

5.3

Varity_R

0.94

gMVP

0.94

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

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