dbSNP rs148589243: CBS:p.Val358Leu (chr21-43060514-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4

The NM_000071.3(CBS):c.1072G>T(p.Val358Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V358M) 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

Not reported in ClinVar

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 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.29656482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.1072G>T	p.Val358Leu	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>T	p.Val358Leu	missense_variant	Exon 12 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000417

AC:

AN:

239690

AF XY:

0.00000761

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000553

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: AC0;AS_VQSR

AF:

0.00

AC:

AN:

41134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

21884

African (AFR)

AF:

0.00

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:

6458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

164

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

21196

Other (OTH)

AF:

0.00

AC:

AN:

2080

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Uncertain

0.040

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Uncertain

0.66

D;D;D;D

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

.;.;.;D

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

-0.97

N;N;N;N

PhyloP100

2.4

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.34

N;N;N;N

REVEL

Uncertain

0.51

Sift

Benign

0.93

T;T;T;T

Sift4G

Benign

0.95

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.37

MutPred

0.49

Loss of ubiquitination at K359 (P = 0.1166);Loss of ubiquitination at K359 (P = 0.1166);Loss of ubiquitination at K359 (P = 0.1166);Loss of ubiquitination at K359 (P = 0.1166);

MVP

0.58

MPC

0.35

ClinPred

0.087

GERP RS

4.2

PromoterAI

0.015

Neutral

(source)

Varity_R

0.24

gMVP

0.79

Mutation Taster

=30/70

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over