Genetic Variant CBS:p.Gly151Arg (chr21-43066243-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 19P and 1B. PS3PM1PP2PP3_StrongPP5_Very_StrongBS2_Supporting

The NM_000071.3(CBS):c.451G>A(p.Gly151Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000178 in 1,349,764 control chromosomes in the GnomAD database, including 4 homozygotes. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001442587: Several publications report experimental evidence indicating that the variant results in severely reduced enzyme activity in-vitro when studied in E. coli or yeast models (e.g. Katsushima_2006, Singh_2010, Mayfield_2012)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G151V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000035 ( 1 hom., cov: 16)

Exomes 𝑓: 0.000016 ( 3 hom. )

Consequence

CBS
NM_000071.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

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, Orphanet, Myriad Women's Health, G2P, Labcorp Genetics (formerly Invitae)

CBS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000071.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001442587: Several publications report experimental evidence indicating that the variant results in severely reduced enzyme activity in-vitro when studied in E. coli or yeast models (e.g. Katsushima_2006, Singh_2010, Mayfield_2012).; SCV001820196: "In vitro functional assays demonstrated loss of CBS enzyme activity (Mayfield et al., 2012; Katsushima et al., 2006)"; SCV001235987: Experimental studies have shown that this missense change affects CBS function (PMID: 16307898, 20066033, 22267502).; SCV002638475: An in vitro assay involving yeast plasmids showed that cells with this alteration required glutathione supplementation to support growth, indicating severe loss of function (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23).; SCV004733765: Functional studies showed that this variant results in impaired enzyme activity and altered assembly of the CBS tetramer (Katsushima et al. 2006. PubMed ID: 16307898; Mayfield et al. 2012. PubMed ID: 22267502).

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

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.

PP5

Variant 21-43066243-C-T is Pathogenic according to our data. 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.

BS2

High Homozygotes in GnomAdExome4 at 3 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.451G>A	p.Gly151Arg	missense splice_region	Exon 5 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.451G>A	p.Gly151Arg	missense splice_region	Exon 5 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.451G>A	p.Gly151Arg	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>A	p.Gly151Arg	missense splice_region	Exon 5 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.451G>A	p.Gly151Arg	missense splice_region	Exon 5 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.451G>A	p.Gly151Arg	missense splice_region	Exon 5 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000346

AC:

AN:

115474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000918

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000350

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248820

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000162

AC:

AN:

1234290

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

616944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18558

American (AMR)

AF:

0.0000236

AC:

AN:

42294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21990

East Asian (EAS)

AF:

0.0000515

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:

0.0000160

AC:

AN:

939638

Other (OTH)

AF:

0.0000388

AC:

AN:

51602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000346

AC:

AN:

115474

Hom.:

Cov.:

AF XY:

0.0000532

AC XY:

AN XY:

56404

show subpopulations

African (AFR)

AF:

0.0000918

AC:

AN:

21798

American (AMR)

AF:

0.00

AC:

AN:

13070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2864

East Asian (EAS)

AF:

0.00

AC:

AN:

4866

South Asian (SAS)

AF:

0.00

AC:

AN:

3872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000350

AC:

AN:

57170

Other (OTH)

AF:

0.00

AC:

AN:

1628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.0000586

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Classic homocystinuria (2)

CBS-related disorder (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Homocystinuria (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.8

PhyloP100

6.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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