rs1061427

chr15-67066140-G-Achr15-67066140-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005902.4(SMAD3):c.-15G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,567,362 control chromosomes in the GnomAD database, including 44,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3864 hom., cov: 31)
  • Exomes 𝑓: 0.24 (40748 hom.)
• Consequence: SMAD3 NM_005902.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.354

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-67066140-G-A is Benign according to our data. Variant chr15-67066140-G-A is described in ClinVar as [Benign]. Clinvar id is 139216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67066140-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.-15G>A		5_prime_UTR_variant	1/9	ENST00000327367.9
SMAD3	NM_001407011.1	c.-15G>A		5_prime_UTR_variant	1/10
SMAD3	NM_001407012.1	c.-15G>A		5_prime_UTR_variant	1/8
SMAD3	NM_001407013.1	c.-15G>A		5_prime_UTR_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.-15G>A		5_prime_UTR_variant	1/9	1	NM_005902.4	P1
SMAD3	ENST00000560424.2	c.-15G>A		5_prime_UTR_variant	1/10	3
SMAD3	ENST00000559460.6	c.-110+2196G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33775 AN: 151458 Hom.: 3870 Cov.: 31

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.219

GnomAD3 exomes AF: 0.232 AC: 41473 AN: 178506 Hom.: 5242 AF XY: 0.241 AC XY: 23287 AN XY: 96594

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.263

Gnomad EAS exome AF: 0.241

Gnomad SAS exome AF: 0.319

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.235 AC: 333285 AN: 1415792 Hom.: 40748 Cov.: 32 AF XY: 0.238 AC XY: 167045 AN XY: 700466

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.314

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.223 AC: 33763 AN: 151570 Hom.: 3864 Cov.: 31 AF XY: 0.226 AC XY: 16695 AN XY: 74032

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.220

Alfa AF: 0.238 Hom.: 848

Bravo AF: 0.207

Asia WGS AF: 0.297 AC: 1032 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	-15G>A in exon 1 of SMAD3: This variant is not expected to have clinical signifi cance because it has been identified in 22.8% (1943/8510) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washing -
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	Aug 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 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:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Aneurysm-osteoarthritis syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Benign	0.96

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: rs1061427; hg19: chr15-67358478;