NM_000071.3:c.1072G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP2

The NM_000071.3(CBS):c.1072G>A(p.Val358Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V358V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 2.39

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 3 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.1072G>A	p.Val358Met	missense_variant	Exon 12 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.1072G>A	p.Val358Met	missense_variant	Exon 12 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad NFE

AF:

0.00

GnomAD2 exomes

AF:

0.000100

AC:

AN:

239690

AF XY:

0.0000989

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000201

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000170

AC:

AN:

41136

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

21886

show subpopulations

African (AFR)

AF:

0.000392

AC:

AN:

2554

American (AMR)

AF:

0.00

AC:

AN:

3730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

884

East Asian (EAS)

AF:

0.00

AC:

AN:

2996

South Asian (SAS)

AF:

0.00

AC:

AN:

6460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

164

European-Non Finnish (NFE)

AF:

0.000236

AC:

AN:

21196

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

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)

AF:

0.00

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:

Alfa

AF:

0.000233

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Feb 23, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 02, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CBS c.1072G>A; p.Val358Met variant (rs148589243), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 193971). This variant is found in the general population with an overall allele frequency of 0.01 % (28/ 271,082 alleles) in the Genome Aggregation Database. The valine at codon 358 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.565). Due to limited information, the clinical significance of the p.Val358Met variant is uncertain at this time. -

Dec 04, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: no PMID) -

Classic homocystinuria

Uncertain:2

Apr 27, 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. -

Jan 06, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1

Oct 15, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CBS c.1072G>A (p.Val358Met) results in a conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain 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 0.0001 in 239690 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CBS causing Homocystinuria (0.0001 vs 0.003), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1072G>A in individuals affected with Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 193971). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jan 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1072G>A (p.V358M) alteration is located in exon 12 (coding exon 10) of the CBS gene. This alteration results from a G to A substitution at nucleotide position 1072, causing the valine (V) at amino acid position 358 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Uncertain:1

Jul 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 358 of the CBS protein (p.Val358Met). This variant is present in population databases (rs148589243, 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: 193971). 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

0.12

BayesDel_addAF

Benign

-0.0031

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;D;D

Eigen

Benign

-0.080

Eigen_PC

Benign

-0.066

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.96

.;.;.;D

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

1.4

L;L;L;L

PhyloP100

2.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Uncertain

0.56

Sift

Benign

0.032

D;D;D;D

Sift4G

Benign

0.083

T;T;T;T

Polyphen

0.77

P;P;P;P

Vest4

0.39

MVP

0.81

MPC

0.58

ClinPred

0.11

GERP RS

4.2

PromoterAI

0.070

Neutral

(source)

Varity_R

0.37

gMVP

0.77

Mutation Taster

=40/60

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over