Genetic Variant CBS:p.Phe99Tyr (chr21-43068529-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBP6

The NM_000071.3(CBS):c.296T>A(p.Phe99Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F99S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 6)

Exomes 𝑓: 0.000035 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.670

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

CBS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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=0.019435287).

BP6

Variant 21-43068529-A-T is Benign according to our data. Variant chr21-43068529-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 405376.

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.296T>A	p.Phe99Tyr	missense	Exon 4 of 17	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.296T>A	p.Phe99Tyr	missense	Exon 4 of 17	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.296T>A	p.Phe99Tyr	missense	Exon 4 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.296T>A	p.Phe99Tyr	missense	Exon 4 of 17	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.296T>A	p.Phe99Tyr	missense	Exon 4 of 17	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.296T>A	p.Phe99Tyr	missense	Exon 4 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

AN:

38986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000984

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

251360

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000352

AC:

AN:

340968

Hom.:

Cov.:

AF XY:

0.0000327

AC XY:

AN XY:

183546

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

8940

American (AMR)

AF:

0.00

AC:

AN:

22662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11414

East Asian (EAS)

AF:

0.00

AC:

AN:

26726

South Asian (SAS)

AF:

0.00

AC:

AN:

43508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1440

European-Non Finnish (NFE)

AF:

0.00000535

AC:

AN:

186800

Other (OTH)

AF:

0.00

AC:

AN:

18880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000205

AC:

AN:

38986

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

17918

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000984

AC:

AN:

8132

American (AMR)

AF:

0.00

AC:

AN:

5278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1144

East Asian (EAS)

AF:

0.00

AC:

AN:

1776

South Asian (SAS)

AF:

0.00

AC:

AN:

984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

18264

Other (OTH)

AF:

0.00

AC:

AN:

500

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000475391), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.344

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:

0.00

Hom.:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Classic homocystinuria (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Uncertain

0.64

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.019

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

0.35

PhyloP100

0.67

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.40

REVEL

Benign

0.24

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.34

MVP

0.29

MPC

0.39

ClinPred

0.014

GERP RS

-3.7

Varity_R

0.12

gMVP

0.76

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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