rs117185005

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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:17

Conservation

PhyloP100: -0.846

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.870C>T	p.Ile290Ile	splice_region_variant, synonymous_variant	Exon 6 of 9	ENST00000327367.9	NP_005893.1	P84022-1A0A024R5Z3Q9P0T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 link	c.870C>T	p.Ile290Ile	splice_region_variant, synonymous_variant	Exon 6 of 9	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2176

AN:

151976

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0157

AC XY:

2100

AN XY:

133952

show subpopulations

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.:

AF XY:

0.0207

AC XY:

15001

AN XY:

725858

show subpopulations

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.:

Cov.:

AF XY:

0.0136

AC XY:

1013

AN XY:

74348

show subpopulations

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.:

Bravo

AF:

0.0125

Asia WGS

AF:

0.00578

AC:

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

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 04, 2022	- -

not provided

Benign:2

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

Aneurysm-osteoarthritis syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 11, 2024	- -
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

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

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