rs1348033858

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_005902.4(SMAD3):c.913G>A(p.Ala305Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SMAD3
NM_005902.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 9.77

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

aneurysm-osteoarthritis syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

SMAD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a region_of_interest Sufficient for interaction with XPO4 (size 53) in uniprot entity SMAD3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005902.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4 link	c.913G>A	p.Ala305Thr	missense_variant	Exon 7 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.913G>A	p.Ala305Thr	missense_variant	Exon 7 of 9	1	NM_005902.4	ENSP00000332973.4		P84022-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:3

Jun 16, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A305T variant (also known as c.913G>A), located in coding exon 7 of the SMAD3 gene, results from a G to A substitution at nucleotide position 913. The alanine at codon 305 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Apr 25, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with threonine at codon 305 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Nov 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 305 of the SMAD3 protein (p.Ala305Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys-Dietz syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 543902). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

SMAD3-related disorder

Uncertain:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SMAD3 c.913G>A variant is predicted to result in the amino acid substitution p.Ala305Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Aneurysm-osteoarthritis syndrome

Uncertain:1

Apr 10, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.86

D;D;D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;.;.;.;.

PhyloP100

9.8

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.7

D;D;D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0030

D;D;D;D;D

Sift4G

Benign

0.097

T;T;T;T;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.90

MutPred

0.60

Loss of sheet (P = 0.302);.;.;.;.;

MVP

0.96

MPC

1.4

ClinPred

1.0

GERP RS

5.3

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.81

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs1348033858

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over