Genetic Variant CBS:p.Phe99Phe (chr21-43068528-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_000071.3(CBS):c.297C>T(p.Phe99Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 6)

Exomes 𝑓: 0.000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.557

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 21-43068528-G-A is Benign according to our data. Variant chr21-43068528-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 519588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.557 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.297C>T	p.Phe99Phe	synonymous_variant	Exon 4 of 17	ENST00000398165.8	NP_000062.1	P35520-1Q9NTF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 link	c.297C>T	p.Phe99Phe	synonymous_variant	Exon 4 of 17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0000258

AC:

AN:

38818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000563

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:

0.0000199

AC:

AN:

251346

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000149

AC:

AN:

336350

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

181038

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

8856

American (AMR)

AF:

0.00

AC:

AN:

22498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11236

East Asian (EAS)

AF:

0.00

AC:

AN:

26496

South Asian (SAS)

AF:

0.0000698

AC:

AN:

43000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1410

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

183970

Other (OTH)

AF:

0.00

AC:

AN:

18624

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.019125), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

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:

0.0000257

AC:

AN:

38906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

17816

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8198

American (AMR)

AF:

0.00

AC:

AN:

5202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1132

East Asian (EAS)

AF:

0.000566

AC:

AN:

1766

South Asian (SAS)

AF:

0.00

AC:

AN:

968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

18310

Other (OTH)

AF:

0.00

AC:

AN:

514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000709

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Aug 04, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Benign:1

Dec 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.39

(source)

DANN

Benign

0.73

PhyloP100

0.56

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over