15-67164997-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005902.4(SMAD3):c.309A>G(p.Leu103=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.875 in 1,614,074 control chromosomes in the GnomAD database, including 618,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L103L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.87 (57780 hom., cov: 34)
  • Exomes 𝑓: 0.88 (560371 hom.)
• Consequence: SMAD3 NM_005902.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 1.30

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 (MetaRNN=1.2951502E-6).
• BP6: Variant 15-67164997-A-G is Benign according to our data. Variant chr15-67164997-A-G is described in ClinVar as [Benign]. Clinvar id is 139217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67164997-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.309A>G	p.Leu103=	synonymous_variant	2/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.309A>G	p.Leu103=	synonymous_variant	2/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes AF: 0.871 AC: 132490 AN: 152198 Hom.: 57735 Cov.: 34

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.910

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.793

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.883

GnomAD3 exomes AF: 0.867 AC: 217954 AN: 251434 Hom.: 94817 AF XY: 0.862 AC XY: 117154 AN XY: 135896

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.944

Gnomad ASJ exome AF: 0.845

Gnomad EAS exome AF: 0.754

Gnomad SAS exome AF: 0.799

Gnomad FIN exome AF: 0.867

Gnomad NFE exome AF: 0.882

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.875 AC: 1279048 AN: 1461758 Hom.: 560371 Cov.: 64 AF XY: 0.873 AC XY: 634533 AN XY: 727186

Gnomad4 AFR exome AF: 0.865

Gnomad4 AMR exome AF: 0.940

Gnomad4 ASJ exome AF: 0.848

Gnomad4 EAS exome AF: 0.808

Gnomad4 SAS exome AF: 0.804

Gnomad4 FIN exome AF: 0.861

Gnomad4 NFE exome AF: 0.883

Gnomad4 OTH exome AF: 0.865

GnomAD4 genome AF: 0.870 AC: 132591 AN: 152316 Hom.: 57780 Cov.: 34 AF XY: 0.869 AC XY: 64729 AN XY: 74480

Gnomad4 AFR AF: 0.862

Gnomad4 AMR AF: 0.910

Gnomad4 ASJ AF: 0.840

Gnomad4 EAS AF: 0.772

Gnomad4 SAS AF: 0.794

Gnomad4 FIN AF: 0.863

Gnomad4 NFE AF: 0.882

Gnomad4 OTH AF: 0.884

Alfa AF: 0.881 Hom.: 67488

Bravo AF: 0.878

TwinsUK AF: 0.884 AC: 3278

ALSPAC AF: 0.888 AC: 3424

ESP6500AA AF: 0.873 AC: 3842

ESP6500EA AF: 0.884 AC: 7598

ExAC AF: 0.863 AC: 104820

Asia WGS AF: 0.782 AC: 2723 AN: 3478

EpiCase AF: 0.886

EpiControl AF: 0.887

ClinVar

Significance: Benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Leu103Leu in exon 2 of SMAD3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 12.7% (560/4402) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1065080). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Nov 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	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	May 09, 2019	- -

Aneurysm-osteoarthritis syndrome Benign:5

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	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Thoracic aortic aneurysm Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	9.0
Dann	Benign	0.96
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0000013	T
MutationTaster	Benign	0.90	P;P;P;P;P
PROVEAN	Pathogenic	-9.0	D
Vest4		0.12
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1065080; hg19: chr15-67457335; COSMIC: COSV59284976; COSMIC: COSV59284976;