rs1555875010

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate

The NM_000071.3(CBS):c.539T>C(p.Val180Ala) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V180M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 4)

Exomes 𝑓: 0.0000075 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.79

Publications

0 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 5 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, 10 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.539T>C	p.Val180Ala	missense_variant	Exon 7 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.539T>C	p.Val180Ala	missense_variant	Exon 7 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000746

AC:

AN:

401926

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

212144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

12652

American (AMR)

AF:

0.00

AC:

AN:

25934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12406

East Asian (EAS)

AF:

0.00

AC:

AN:

31006

South Asian (SAS)

AF:

0.00

AC:

AN:

46868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1732

European-Non Finnish (NFE)

AF:

0.0000134

AC:

AN:

223214

Other (OTH)

AF:

0.00

AC:

AN:

22990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Classic homocystinuria

Uncertain:1

Feb 20, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;D;D;D

Eigen

Benign

-0.032

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

.;.;.;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.34

N;N;N;N

PhyloP100

7.8

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Pathogenic

0.78

Sift

Benign

0.17

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.054

B;B;B;B

Vest4

0.69

MutPred

0.81

Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);

MVP

0.79

MPC

0.74

ClinPred

0.95

GERP RS

4.7

Varity_R

0.76

gMVP

0.73

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over