chr15-67066140-G-A

Position:

chr15-67066140-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.354

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:

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ACMG classification

Classification made for transcript

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	Effect	#exon/exons	MANE	Protein
SMAD3	NM_005902.4 linkuse as main transcript	c.-15G>A	5_prime_UTR_variant	1/9	ENST00000327367.9	NP_005893.1
SMAD3	NM_001407011.1 linkuse as main transcript	c.-15G>A	5_prime_UTR_variant	1/10		NP_001393940.1
SMAD3	NM_001407012.1 linkuse as main transcript	c.-15G>A	5_prime_UTR_variant	1/8		NP_001393941.1
SMAD3	NM_001407013.1 linkuse as main transcript	c.-15G>A	5_prime_UTR_variant	1/8		NP_001393942.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 linkuse as main transcript	c.-15G>A	5_prime_UTR_variant	1/9	1	NM_005902.4	ENSP00000332973	P1	P84022-1
SMAD3	ENST00000560424.2 linkuse as main transcript	c.-15G>A	5_prime_UTR_variant	1/10	3		ENSP00000455540
SMAD3	ENST00000559460.6 linkuse as main transcript	c.-110+2196G>A	intron_variant		4		ENSP00000453082

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33775

AN:

151458

Hom.:

3870

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.238

AC XY:

167045

AN XY:

700466

show subpopulations

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.:

AF XY:

0.226

AC XY:

16695

AN XY:

74032

show subpopulations

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -
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 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

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

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

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