rs1061427

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.-15G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,567,362 control chromosomes in the GnomAD database, including 44,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3864 hom., cov: 31)

Exomes 𝑓: 0.24 ( 40748 hom. )

Consequence

SMAD3
NM_005902.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.354

Publications

16 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=-0.6).

BP6

Variant 15-67066140-G-A is Benign according to our data. Variant chr15-67066140-G-A is described in ClinVar as [Benign]. Clinvar id is 139216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.-15G>A	5_prime_UTR_variant	Exon 1 of 9	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0
SMAD3	NM_001407011.1 link	c.-15G>A	5_prime_UTR_variant	Exon 1 of 10		NP_001393940.1
SMAD3	NM_001407012.1 link	c.-15G>A	5_prime_UTR_variant	Exon 1 of 8		NP_001393941.1
SMAD3	NM_001407013.1 link	c.-15G>A	5_prime_UTR_variant	Exon 1 of 8		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 link	c.-15G>A		5_prime_UTR_variant	Exon 1 of 9	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33775

AN:

151458

Hom.:

3870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.156

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.307

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.240

Gnomad OTH

AF:

0.219

GnomAD2 exomes

AF:

0.232

AC:

41473

AN:

178506

AF XY:

0.241

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.263

Gnomad EAS exome

AF:

0.241

Gnomad FIN exome

AF:

0.282

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.235

AC:

333285

AN:

1415792

Hom.:

40748

Cov.:

AF XY:

0.238

AC XY:

167045

AN XY:

700466

show subpopulations

African (AFR)

AF:

0.187

AC:

6047

AN:

32274

American (AMR)

AF:

0.119

AC:

4564

AN:

38432

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

6683

AN:

25382

East Asian (EAS)

AF:

0.202

AC:

7493

AN:

37156

South Asian (SAS)

AF:

0.314

AC:

25478

AN:

81228

European-Finnish (FIN)

AF:

0.280

AC:

13766

AN:

49120

Middle Eastern (MID)

AF:

0.248

AC:

1029

AN:

4144

European-Non Finnish (NFE)

AF:

0.233

AC:

254272

AN:

1089532

Other (OTH)

AF:

0.238

AC:

13953

AN:

58524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

12949

25897

38846

51794

64743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.223

AC:

33763

AN:

151570

Hom.:

3864

Cov.:

AF XY:

0.226

AC XY:

16695

AN XY:

74032

show subpopulations

African (AFR)

AF:

0.192

AC:

7959

AN:

41400

American (AMR)

AF:

0.156

AC:

2377

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

880

AN:

3466

East Asian (EAS)

AF:

0.232

AC:

1182

AN:

5088

South Asian (SAS)

AF:

0.305

AC:

1469

AN:

4822

European-Finnish (FIN)

AF:

0.275

AC:

2893

AN:

10510

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.240

AC:

16235

AN:

67710

Other (OTH)

AF:

0.220

AC:

464

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1328

2656

3984

5312

6640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.237

Hom.:

860

Bravo

AF:

0.207

Asia WGS

AF:

0.297

AC:

1032

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

-15G>A in exon 1 of SMAD3: This variant is not expected to have clinical signifi cance because it has been identified in 22.8% (1943/8510) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washing -

Aug 16, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 13, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.60

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.35

Mutation Taster

=300/0

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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rs1061427

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