Genetic Variant CBS:c.317-477G>A (chr21-43066854-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000071.3(CBS):c.317-477G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.071 ( 1225 hom., cov: 16)

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.628

Publications

61 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3 link	c.317-477G>A		intron_variant	Intron 4 of 16	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.317-477G>A		intron_variant	Intron 4 of 16	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0715

AC:

6202

AN:

86766

Hom.:

1224

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.0424

Gnomad AMR

AF:

0.0527

Gnomad ASJ

AF:

0.0491

Gnomad EAS

AF:

0.0118

Gnomad SAS

AF:

0.0319

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0260

Gnomad NFE

AF:

0.0487

Gnomad OTH

AF:

0.0629

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0715

AC:

6203

AN:

86792

Hom.:

1225

Cov.:

AF XY:

0.0688

AC XY:

2993

AN XY:

43520

show subpopulations

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

African (AFR)

AF:

0.311

AC:

2882

AN:

9252

American (AMR)

AF:

0.0525

AC:

555

AN:

10572

Ashkenazi Jewish (ASJ)

AF:

0.0491

AC:

115

AN:

2344

East Asian (EAS)

AF:

0.0118

AC:

AN:

4490

South Asian (SAS)

AF:

0.0319

AC:

112

AN:

3514

European-Finnish (FIN)

AF:

0.0165

AC:

143

AN:

8662

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.0487

AC:

2231

AN:

45828

Other (OTH)

AF:

0.0618

AC:

AN:

1262

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.264

Heterozygous variant carriers

446

892

1339

1785

2231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.468

Hom.:

26787

Asia WGS

AF:

0.283

AC:

985

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.18

(source)

DANN

Benign

0.78

PhyloP100

-0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over