Variant rs786204686 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000071.3(CBS):c.1316G>A(p.Arg439Gln) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 1.40

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a domain CBS (size 58) in uniprot entity CBS_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000071.3

BP4

Computational evidence support a benign effect (MetaRNN=0.42296112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.1316G>A	p.Arg439Gln	missense_variant	14/17	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.1316G>A	p.Arg439Gln	missense_variant	14/17	1	NM_000071.3	ENSP00000381231	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000234

AC:

AN:

171116

Hom.:

AF XY:

0.0000330

AC XY:

AN XY:

91032

show subpopulations

Gnomad AFR exome

AF:

0.0000997

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:

0.0000430

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000913

Hom.:

ExAC

AF:

0.0000169

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Classic homocystinuria

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	literature only	Counsyl	Dec 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	GeneDx	Jul 26, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies have not shown a significant impact on protein function (Kozich et al., 2010; Hnzda et al., 2012; Mayfield et al., 2012); This variant is associated with the following publications: (PMID: 22267502, 20490928, 22069143, 9156316, 19429038, 20506325) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2015	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 01, 2023

Variant summary: CBS c.1316G>A (p.Arg439Gln) results in a conservative amino acid change located in the CBS domain (IPR000644) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 171116 control chromosomes (gnomAD). The variant, c.1316G>A, has been reported in the literature in at least three individuals affected with Homocystinuria (Tsai_1997, Dawson_1997, Gaustadnes_2002), however two of these patients also carried a pathogenic variant (c.430G>A (p.Glu144Lys)) in cis. Multiple publications reported experimental evidence evaluating an impact on protein function, and although in an early study the variant was found to result in a moderately reduced enzyme activity (~30% of WT) in a bacterial expression system (Dawson_1997)), later studies found activities similar to wild type in bacterial-, yeast- and mammalian systems (Mayfield_2012, Kopecka_2011, Hnizda_2012, Melenovska_2015). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=3) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2023

The p.R439Q variant (also known as c.1316G>A), located in coding exon 12 of the CBS gene, results from a G to A substitution at nucleotide position 1316. The arginine at codon 439 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in cis with an additional alteration in CBS in individuals with homocystinuria (Dawson PA et al. Eur J Hum Genet, 1997;5:15-21; Tsai MY et al. Mol Diagn, 1997 Jun;2:129-133; Gaustadnes M et al. Hum Mutat, 2002 Aug;20:117-26). In vitro assays showed this alteration may not impact protein function (Dawson PA et al. Eur J Hum Genet, 1997;5:15-21; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). This amino acid position is not 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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 26, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 439 of the CBS protein (p.Arg439Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with homocystinuria, co-occuring in cis with another likely pathogenic variant (p.Glu144Lys). This variant also co-occurs in trans with other pathogenic variants in individuals with homocystinuria (PMID: 9156316, 10462600, 12124992). 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: 189088). 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. Experimental studies have shown that this missense change does not substantially affect CBS function (PMID: 9156316, 20490928, 20506325, 22069143, 22267502). 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

0.075

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;D;D

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.96

.;.;.;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.42

T;T;T;T

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.9

L;L;L;L

MutationTaster

Benign

0.82

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

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.29

T;T;T;T

Polyphen

0.21

B;B;B;B

Vest4

0.34

MVP

0.72

MPC

0.41

ClinPred

0.10

GERP RS

4.7

Varity_R

0.51

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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