rs35874463

Positions:

chr15-67165360-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_005902.4(SMAD3):c.508A>G(p.Ile170Val) variant causes a missense change. The variant allele was found at a frequency of 0.0491 in 1,614,100 control chromosomes in the GnomAD database, including 2,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 117 hom., cov: 33)

Exomes 𝑓: 0.051 ( 2140 hom. )

Consequence

SMAD3
NM_005902.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 4.95

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 links:

SMAD3 (HGNC:):

SMAD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD3. . Gene score misZ 3.4782 (greater than the threshold 3.09). Trascript score misZ 4.3526 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, aneurysm-osteoarthritis syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.00407815).

BP6

Variant 15-67165360-A-G is Benign according to our data. Variant chr15-67165360-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 139212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67165360-A-G is described in Lovd as [Benign]. Variant chr15-67165360-A-G is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4 linkuse as main transcript	c.508A>G	p.Ile170Val	missense_variant	3/9	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 linkuse as main transcript	c.508A>G	p.Ile170Val	missense_variant	3/9	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.0342

AC:

5203

AN:

152160

Hom.:

117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0235

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0410

Gnomad FIN

AF:

0.0469

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0506

Gnomad OTH

AF:

0.0339

GnomAD3 exomes

AF:

0.0396

AC:

9960

AN:

251386

Hom.:

275

AF XY:

0.0411

AC XY:

5587

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00947

Gnomad AMR exome

AF:

0.0215

Gnomad ASJ exome

AF:

0.0558

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0425

Gnomad FIN exome

AF:

0.0449

Gnomad NFE exome

AF:

0.0525

Gnomad OTH exome

AF:

0.0415

GnomAD4 exome

AF:

0.0506

AC:

74008

AN:

1461822

Hom.:

2140

Cov.:

AF XY:

0.0506

AC XY:

36798

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00908

Gnomad4 AMR exome

AF:

0.0214

Gnomad4 ASJ exome

AF:

0.0552

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0436

Gnomad4 FIN exome

AF:

0.0430

Gnomad4 NFE exome

AF:

0.0558

Gnomad4 OTH exome

AF:

0.0484

GnomAD4 genome

AF:

0.0341

AC:

5198

AN:

152278

Hom.:

117

Cov.:

AF XY:

0.0335

AC XY:

2492

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.0234

Gnomad4 ASJ

AF:

0.0568

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0405

Gnomad4 FIN

AF:

0.0469

Gnomad4 NFE

AF:

0.0506

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.0475

Hom.:

169

Bravo

AF:

0.0319

TwinsUK

AF:

0.0488

AC:

181

ALSPAC

AF:

0.0573

AC:

221

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.0547

AC:

470

ExAC

AF:

0.0402

AC:

4883

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0541

EpiControl

AF:

0.0528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Ile170Val in exon 3 of SMAD3: This variant is not expected to have clinical sign ificance because it has been identified in 5.5% (470/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs35874463). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2019	Variant summary: SMAD3 c.508A>G (p.Ile170Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.04 in 251386 control chromosomes in the gnomAD database, including 275 homozygotes. The observed variant frequency is approximately 1056 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD3 causing Aortopathy phenotype (3.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.508A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=5)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 25, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Aneurysm-osteoarthritis syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Loeys-Dietz syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 07, 2022

- -

Thoracic aortic aneurysm

Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

.;T;T;.;T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.039

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

MetaRNN

Benign

0.0041

T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.81

.;L;.;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.40

N;N;N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.33

T;T;T;T;T;T

Sift4G

Benign

0.66

T;T;T;T;T;T

Polyphen

0.0

.;B;.;.;.;.

Vest4

0.12, 0.20, 0.26

MPC

1.0

ClinPred

0.011

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.098

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over