rs35874463

chr15-67165360-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. I170I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (117 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2140 hom.)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 4.95

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMAD3
• 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	UniProt
SMAD3	NM_005902.4	c.508A>G	p.Ile170Val	missense_variant	3/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.508A>G	p.Ile170Val	missense_variant	3/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5203 AN: 152160 Hom.: 117 Cov.: 33

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

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.: 34 AF XY: 0.0506 AC XY: 36798 AN XY: 727214

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.: 33 AF XY: 0.0335 AC XY: 2492 AN XY: 74456

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: 56

ESP6500EA AF: 0.0547 AC: 470

ExAC AF: 0.0402 AC: 4883

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0541

EpiControl AF: 0.0528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -
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, 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	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	Invitae	Feb 01, 2024	- -
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. -

Aneurysm-osteoarthritis syndrome Benign:3

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. -
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	Feb 05, 2024	- -

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

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

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	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.83	D
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	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.40	N;N;N;N;N;N
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	T
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

Other links and lift over

dbSNP: rs35874463; hg19: chr15-67457698; COSMIC: COSV59281888; COSMIC: COSV59281888;