rs117185005

Positions:

• chr15-67181452-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000327367.9(SMAD3):​c.870C>T​(p.Ile290=) 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 ENST00000327367.9 splice_region, synonymous
• Scores: Splicing: ADA: 0.001484
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.846

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 -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 [Likely_benign]. Clinvar id is 139213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67181452-C-T is described in Lovd as [Benign]. Variant chr15-67181452-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.870C>T	p.Ile290=	splice_region_variant, synonymous_variant	6/9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.870C>T	p.Ile290=	splice_region_variant, synonymous_variant	6/9	1	NM_005902.4	ENSP00000332973	P1

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

GnomAD3 exomes AF: 0.0155 AC: 3815 AN: 246116 Hom.: 39 AF XY: 0.0157 AC XY: 2100 AN XY: 133952

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 SAS exome AF: 0.0125

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

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.00673

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.0245

Gnomad4 OTH exome AF: 0.0168

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

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.0206

Gnomad4 NFE AF: 0.0234

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.0209 Hom.: 54

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:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2015	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	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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)	-	- -

Aneurysm-osteoarthritis syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

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

Jun 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.3
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

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