15-67181441-C-T

Position:

chr15-67181441-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_005902.4(SMAD3):c.859C>T(p.Arg287Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R287Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SMAD3
NM_005902.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.667

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 Pathogenic. Variant got 19 ACMG points.

PM1

In a region_of_interest Sufficient for interaction with XPO4 (size 53) in uniprot entity SMAD3_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_005902.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-67181442-G-A is described in Lovd as [Likely_pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMAD3. . Gene score misZ 3.4782 (greater than the threshold 3.09). Trascript score misZ 4.3526 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, aneurysm-osteoarthritis syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 15-67181441-C-T is Pathogenic according to our data. Variant chr15-67181441-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67181441-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD3	NM_005902.4 linkuse as main transcript	c.859C>T	p.Arg287Trp	missense_variant	6/9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9 linkuse as main transcript	c.859C>T	p.Arg287Trp	missense_variant	6/9	1	NM_005902.4	ENSP00000332973	P1	P84022-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460896

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726752

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 287 of the SMAD3 protein (p.Arg287Trp). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 30306). This missense change has been observed in individuals with aortic aneurysm and osteoarthritis and aneurysms and osteoarthritis syndrome, thoracic aortic aneurysm and dissection, or clinical features of Loeys-Dietz syndrome (PMID: 21217753, 25644172, 29717556; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 16, 2020	The p.R287W pathogenic mutation (also known as c.859C>T), located in coding exon 6 of the SMAD3 gene, results from a C to T substitution at nucleotide position 859. The arginine at codon 287 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in association with several families with thoracic aortic aneurysms and dissections (TAAD) and osteo-arthritis and has been shown to segregate with disease (van de Laar IM et al. Nat. Genet., 2011 Feb;43:121-6; van de Laar IM et al. J. Med. Genet., 2012 Jan;49:47-57; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Backer J et al. Mol Genet Genomic Med, 2018 May; Ambry internal data). Based on internal structural assessment, this alteration may result in disruption of the interfacial surface of SMAD3 with SMAD2/3/4 (Chacko BM. et al. Mol. Cell. 2004 Sept;15(5):813-23, Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 30306; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24583347, 29717556, 30661052, 23554019, 22167769, 17994767, 26355014, 22803640, 24135912, 26221609, 21217753, 25644172, 28185953) -

Aneurysm-osteoarthritis syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 30, 2024	Criteria applied: PS4,PM5,PM2_SUP,PP2,PP3 -

Ehlers-Danlos syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;D;.;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.21

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

H;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.7

D;D;D;D;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.98

MutPred

0.92

Gain of catalytic residue at L285 (P = 0.037);.;.;.;.;.;

MVP

0.99

MPC

2.5

ClinPred

1.0

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.95

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