rs12595334

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005902.4(SMAD3):c.*2282C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 233,046 control chromosomes in the GnomAD database, including 7,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3833 hom., cov: 32)

Exomes 𝑓: 0.27 ( 3350 hom. )

Consequence

SMAD3
NM_005902.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.535

Publications

22 publications found

Variant links:

Genes affected

SMAD3 (HGNC:6769): (SMAD family member 3) The SMAD family of proteins are a group of intracellular signal transducer proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. The SMAD3 protein functions in the transforming growth factor-beta signaling pathway, and transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. This protein forms a complex with other SMAD proteins and binds DNA, functioning both as a transcription factor and tumor suppressor. Mutations in this gene are associated with aneurysms-osteoarthritis syndrome and Loeys-Dietz Syndrome 3. [provided by RefSeq, May 2022]

SMAD3 Gene-Disease associations (from GenCC):

aneurysm-osteoarthritis syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

SMAD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 15-67192818-C-T is Benign according to our data. Variant chr15-67192818-C-T is described in ClinVar as Benign. ClinVar VariationId is 316934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.*2282C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 link	c.*2282C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30667

AN:

152060

Hom.:

3832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0739

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.332

Gnomad EAS

AF:

0.462

Gnomad SAS

AF:

0.287

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.223

Gnomad OTH

AF:

0.238

GnomAD4 exome

AF:

0.267

AC:

21604

AN:

80868

Hom.:

3350

Cov.:

AF XY:

0.267

AC XY:

9920

AN XY:

37186

show subpopulations

African (AFR)

AF:

0.0783

AC:

304

AN:

3884

American (AMR)

AF:

0.312

AC:

778

AN:

2494

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

1720

AN:

5106

East Asian (EAS)

AF:

0.477

AC:

5490

AN:

11508

South Asian (SAS)

AF:

0.296

AC:

207

AN:

700

European-Finnish (FIN)

AF:

0.155

AC:

AN:

Middle Eastern (MID)

AF:

0.292

AC:

143

AN:

490

European-Non Finnish (NFE)

AF:

0.228

AC:

11362

AN:

49876

Other (OTH)

AF:

0.236

AC:

1591

AN:

6752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

783

1565

2348

3130

3913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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

AF:

0.202

AC:

30686

AN:

152178

Hom.:

3833

Cov.:

AF XY:

0.207

AC XY:

15367

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0739

AC:

3066

AN:

41516

American (AMR)

AF:

0.317

AC:

4838

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

1151

AN:

3468

East Asian (EAS)

AF:

0.463

AC:

2393

AN:

5170

South Asian (SAS)

AF:

0.286

AC:

1379

AN:

4826

European-Finnish (FIN)

AF:

0.182

AC:

1923

AN:

10594

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.223

AC:

15155

AN:

68010

Other (OTH)

AF:

0.239

AC:

505

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1209

2419

3628

4838

6047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.228

Hom.:

5650

Bravo

AF:

0.207

Asia WGS

AF:

0.335

AC:

1165

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24583347) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aneurysm-osteoarthritis syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.6

(source)

DANN

Benign

0.47

PhyloP100

0.54

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over