dbSNP rs373782713: CBS:p.Gly151Trp (chr21-43066243-C-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM5PP2PP3_Strong

The NM_000071.3(CBS):c.451G>T(p.Gly151Trp) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G151R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 16)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.84

Publications

10 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: ClinGen, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet

CBS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066243-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 863694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBS	NM_000071.3	MANE Select	c.451G>T	p.Gly151Trp	missense splice_region	Exon 5 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.451G>T	p.Gly151Trp	missense splice_region	Exon 5 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.451G>T	p.Gly151Trp	missense splice_region	Exon 5 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBS	ENST00000398165.8	TSL:1 MANE Select	c.451G>T	p.Gly151Trp	missense splice_region	Exon 5 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.451G>T	p.Gly151Trp	missense splice_region	Exon 5 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.451G>T	p.Gly151Trp	missense splice_region	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248820

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000619

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1234290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

616944

African (AFR)

AF:

0.00

AC:

AN:

18558

American (AMR)

AF:

0.00

AC:

AN:

42294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21990

East Asian (EAS)

AF:

0.00

AC:

AN:

38862

South Asian (SAS)

AF:

0.00

AC:

AN:

76528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4432

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

939638

Other (OTH)

AF:

0.00

AC:

AN:

51602

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.8

PhyloP100

6.8

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.96

Loss of disorder (P = 0.0524)

MVP

0.93

MPC

1.2

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.99

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over