rs117185005

Variant names:

• chr15-67181452-C-T
• rs117185005
• NM_005902.4:c.870C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005902.4(SMAD3):​c.870C>T​(p.Ile290Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,611,190 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (29 hom., cov: 32)
  • Exomes 𝑓: 0.021 (381 hom.)
• Consequence: SMAD3 NM_005902.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.001484
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.846
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-67181452-C-T is Benign according to our data. Variant chr15-67181452-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.846 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0143 (2176/152090) while in subpopulation NFE AF = 0.0234 (1593/67966). AF 95% confidence interval is 0.0225. There are 29 homozygotes in GnomAd4. There are 1013 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2176 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.870C>T	p.Ile290Ile	splice_region synonymous	Exon 6 of 9	NP_005893.1
	SMAD3	NM_001407011.1		c.870C>T	p.Ile290Ile	splice_region synonymous	Exon 6 of 10	NP_001393940.1
	SMAD3	NM_001145103.2		c.738C>T	p.Ile246Ile	splice_region synonymous	Exon 6 of 9	NP_001138575.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.870C>T	p.Ile290Ile	splice_region synonymous	Exon 6 of 9	ENSP00000332973.4
	SMAD3	ENST00000439724.7	TSL:1	c.738C>T	p.Ile246Ile	splice_region synonymous	Exon 6 of 9	ENSP00000401133.3
	SMAD3	ENST00000540846.6	TSL:1	c.555C>T	p.Ile185Ile	splice_region synonymous	Exon 6 of 9	ENSP00000437757.2

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2176 AN: 151976 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.0155 AC: 3815 AN: 246116 AF XY: 0.0157

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00715

Gnomad ASJ exome AF: 0.000804

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0211 AC: 30855 AN: 1459100 Hom.: 381 Cov.: 32 AF XY: 0.0207 AC XY: 15001 AN XY: 725858

African (AFR) AF: 0.00293 AC: 98 AN: 33460

American (AMR) AF: 0.00673 AC: 301 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0117 AC: 1012 AN: 86180

European-Finnish (FIN) AF: 0.0218 AC: 1130 AN: 51946

Middle Eastern (MID) AF: 0.00300 AC: 16 AN: 5332

European-Non Finnish (NFE) AF: 0.0245 AC: 27254 AN: 1111376

Other (OTH) AF: 0.0168 AC: 1015 AN: 60276

GnomAD4 genome AF: 0.0143 AC: 2176 AN: 152090 Hom.: 29 Cov.: 32 AF XY: 0.0136 AC XY: 1013 AN XY: 74348

African (AFR) AF: 0.00378 AC: 157 AN: 41502

American (AMR) AF: 0.00497 AC: 76 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4794

European-Finnish (FIN) AF: 0.0206 AC: 218 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0234 AC: 1593 AN: 67966

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.0207 Hom.: 123

Bravo AF: 0.0125

Asia WGS AF: 0.00578 AC: 22 AN: 3476

EpiCase AF: 0.0216

EpiControl AF: 0.0216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 22, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SMAD3 c.870C>T (p.Ile290Ile) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.016 in 246116 control chromosomes, predominantly at a frequency of 0.024 within the Non-Finnish European subpopulation in the gnomAD database, including 29 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 640 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.870C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions (evaluation after 2014) cite the variant four times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 02, 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.

Familial thoracic aortic aneurysm and aortic dissection Benign:5

Mar 06, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 04, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aneurysm-osteoarthritis syndrome Benign:2

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loeys-Dietz syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ehlers-Danlos syndrome Benign:1

Jun 30, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.3
DANN	Benign	0.65
PhyloP100		-0.85
Mutation Taster		=56/44	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.036
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

Other links and lift over

dbSNP: rs117185005; hg19: chr15-67473790; COSMIC: COSV99046575; COSMIC: COSV99046575;