Genetic Variant CBS:p.Ala114Val (chr21-43066353-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM5PP2PP5_Very_StrongBS2_Supporting

The NM_000071.3(CBS):c.341C>T(p.Ala114Val) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., cov: 7)

Exomes 𝑓: 0.00011 ( 6 hom. )

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 8.69

Publications

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

CBS links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066354-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 429655.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.

PP5

Variant 21-43066353-G-A is Pathogenic according to our data. Variant chr21-43066353-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.341C>T	p.Ala114Val	missense	Exon 5 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.341C>T	p.Ala114Val	missense	Exon 5 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.341C>T	p.Ala114Val	missense	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.341C>T	p.Ala114Val	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.341C>T	p.Ala114Val	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.341C>T	p.Ala114Val	missense	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000504

AC:

AN:

59574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000620

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000211

AC:

AN:

251024

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

AN:

754022

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

391174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

14126

American (AMR)

AF:

0.000156

AC:

AN:

38450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18816

East Asian (EAS)

AF:

0.000168

AC:

AN:

35614

South Asian (SAS)

AF:

0.00

AC:

AN:

66212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2728

European-Non Finnish (NFE)

AF:

0.000135

AC:

AN:

509476

Other (OTH)

AF:

0.0000842

AC:

AN:

35632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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

AF:

0.0000503

AC:

AN:

59606

Hom.:

Cov.:

AF XY:

0.0000353

AC XY:

AN XY:

28290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

7982

American (AMR)

AF:

0.000139

AC:

AN:

7194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1638

East Asian (EAS)

AF:

0.00

AC:

AN:

3092

South Asian (SAS)

AF:

0.00

AC:

AN:

1692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

112

European-Non Finnish (NFE)

AF:

0.0000620

AC:

AN:

32262

Other (OTH)

AF:

0.00

AC:

AN:

802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000184

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000889

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (10)

not provided (5)

CBS-related disorder (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Homocystinuria (1)

Homocystinuria, pyridoxine-responsive (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.67

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.77

PhyloP100

8.7

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.88

Sift

Uncertain

0.017

Sift4G

Uncertain

0.020

Polyphen

0.97

Vest4

0.97

MVP

0.91

MPC

0.75

ClinPred

0.22

GERP RS

5.4

Varity_R

0.66

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over