rs1005584

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is . The variant received -7 ACMG points: 1P and 8B. PP3BP6_Very_Strong

The NM_000071.3(CBS):c.1468-98G>A variant causes a intron 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 Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 49 hom., cov: 3)

Exomes 𝑓: 0.0032 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.00

Publications

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

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: Benign. The variant received -7 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 21-43056985-C-T is Benign according to our data. Variant chr21-43056985-C-T is described in ClinVar as Benign. ClinVar VariationId is 1235563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	Effect	Exon Rank	Protein	UniProt
CBS	NM_000071.3	MANE Select	c.1468-98G>A	intron	N/A	NP_000062.1	P35520-1
CBS	NM_001178008.3		c.1468-98G>A	intron	N/A	NP_001171479.1	P35520-1
CBS	NM_001178009.3		c.1468-98G>A	intron	N/A	NP_001171480.1	P35520-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CBS	ENST00000398165.8	TSL:1 MANE Select	c.1468-98G>A	intron	N/A	ENSP00000381231.4	P35520-1
CBS	ENST00000352178.9	TSL:1	c.1468-98G>A	intron	N/A	ENSP00000344460.5	P35520-1
CBS	ENST00000359624.7	TSL:1	c.1468-98G>A	intron	N/A	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.0740

AC:

453

AN:

6124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.248

Gnomad AMI

AF:

0.0500

Gnomad AMR

AF:

0.0261

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.0147

Gnomad MID

AF:

0.0270

Gnomad NFE

AF:

0.0556

Gnomad OTH

AF:

0.0887

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00320

AC:

AN:

20970

Hom.:

AF XY:

0.00338

AC XY:

AN XY:

11552

show subpopulations

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

African (AFR)

AF:

0.0233

AC:

AN:

American (AMR)

AF:

0.00330

AC:

AN:

4244

Ashkenazi Jewish (ASJ)

AF:

0.00224

AC:

AN:

446

East Asian (EAS)

AF:

0.000729

AC:

AN:

1372

South Asian (SAS)

AF:

0.00541

AC:

AN:

5176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

834

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00236

AC:

AN:

7630

Other (OTH)

AF:

0.00183

AC:

AN:

1090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.283

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0748

AC:

458

AN:

6124

Hom.:

Cov.:

AF XY:

0.0708

AC XY:

205

AN XY:

2894

show subpopulations

African (AFR)

AF:

0.253

AC:

172

AN:

680

American (AMR)

AF:

0.0260

AC:

AN:

1616

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

AN:

124

East Asian (EAS)

AF:

0.119

AC:

AN:

520

South Asian (SAS)

AF:

0.112

AC:

AN:

374

European-Finnish (FIN)

AF:

0.0147

AC:

AN:

544

Middle Eastern (MID)

AF:

0.0286

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0557

AC:

113

AN:

2030

Other (OTH)

AF:

0.0794

AC:

AN:

126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.0668

Hom.:

761

Asia WGS

AF:

0.0950

AC:

332

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.53

Position offset: -1

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