Genetic Variant NM_000071.3:c.573G>A (chr21-43065480-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000071.3(CBS):c.573G>A(p.Thr191Thr) 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 0.0061 ( 5 hom., cov: 4)

Exomes 𝑓: 0.0088 ( 802 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -6.46

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 21-43065480-C-T is Benign according to our data. Variant chr21-43065480-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.45 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00881 (3668/416138) while in subpopulation MID AF = 0.0402 (73/1814). AF 95% confidence interval is 0.0328. There are 802 homozygotes in GnomAdExome4. There are 1959 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 802 AR gene

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
CBS	NM_000071.3	MANE Select	c.573G>A	p.Thr191Thr	synonymous	Exon 7 of 17	NP_000062.1
CBS	NM_001178008.3		c.573G>A	p.Thr191Thr	synonymous	Exon 7 of 17	NP_001171479.1
CBS	NM_001178009.3		c.573G>A	p.Thr191Thr	synonymous	Exon 7 of 18	NP_001171480.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CBS	ENST00000398165.8	TSL:1 MANE Select	c.573G>A	p.Thr191Thr	synonymous	Exon 7 of 17	ENSP00000381231.4
CBS	ENST00000352178.9	TSL:1	c.573G>A	p.Thr191Thr	synonymous	Exon 7 of 17	ENSP00000344460.5
CBS	ENST00000359624.7	TSL:1	c.573G>A	p.Thr191Thr	synonymous	Exon 7 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

108

AN:

17188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.0381

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00465

Gnomad FIN

AF:

0.000638

Gnomad MID

AF:

0.0652

Gnomad NFE

AF:

0.00678

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00585

AC:

1457

AN:

248930

AF XY:

0.00622

show subpopulations

Gnomad AFR exome

AF:

0.00541

Gnomad AMR exome

AF:

0.00278

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00617

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.00881

AC:

3668

AN:

416138

Hom.:

802

Cov.:

AF XY:

0.00890

AC XY:

1959

AN XY:

220148

show subpopulations

African (AFR)

AF:

0.00724

AC:

AN:

13116

American (AMR)

AF:

0.00409

AC:

115

AN:

28122

Ashkenazi Jewish (ASJ)

AF:

0.0396

AC:

523

AN:

13214

East Asian (EAS)

AF:

0.00

AC:

AN:

31190

South Asian (SAS)

AF:

0.0110

AC:

531

AN:

48476

European-Finnish (FIN)

AF:

0.000380

AC:

AN:

26294

Middle Eastern (MID)

AF:

0.0402

AC:

AN:

1814

European-Non Finnish (NFE)

AF:

0.00905

AC:

2083

AN:

230154

Other (OTH)

AF:

0.0100

AC:

238

AN:

23758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

117

233

350

466

583

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:

0.00614

AC:

106

AN:

17274

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

AN XY:

8070

show subpopulations

African (AFR)

AF:

0.00614

AC:

AN:

4074

American (AMR)

AF:

0.00448

AC:

AN:

2008

Ashkenazi Jewish (ASJ)

AF:

0.0381

AC:

AN:

420

East Asian (EAS)

AF:

0.00

AC:

AN:

1008

South Asian (SAS)

AF:

0.00459

AC:

AN:

436

European-Finnish (FIN)

AF:

0.000638

AC:

AN:

1568

Middle Eastern (MID)

AF:

0.0652

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00678

AC:

AN:

7378

Other (OTH)

AF:

0.00

AC:

AN:

246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.00733

Hom.:

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00829

EpiControl

AF:

0.00842

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Classic homocystinuria (2)

Connective tissue disorder (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.56

(source)

DANN

Benign

0.86

PhyloP100

-6.5

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over