rs863223740

Positions:

chr15-67181385-G-A

Variant summary

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

The NM_005902.4(SMAD3):c.803G>A(p.Arg268His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. R268C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMAD3
NM_005902.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.87

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 hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr15-67181384-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.988

PP5

Variant 15-67181385-G-A is Pathogenic according to our data. Variant chr15-67181385-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67181385-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4 linkuse as main transcript	c.803G>A	p.Arg268His	missense_variant	6/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9 linkuse as main transcript	c.803G>A	p.Arg268His	missense_variant	6/9	1	NM_005902.4	P1	P84022-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	Nov 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 268 of the SMAD3 protein (p.Arg268His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SMAD3-related conditions (PMID: 25944730, 26854089; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 213766). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg268 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10092624, 29907982; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 30, 2015	The p.Arg268His variant has been reported in 2 adults with aortic dilation and a neurysm and segregated with disease in 1 affected relative (Chung 2013 abstract, Zarate 2015). This variant was absent from large population studies. In vitro f unctional studies provide some evidence that the p.Arg268His variant impacts the levels of intracellular SMAD3 protein, which may have some effect on the downst ream pathway (Chung 2013). However, these types of assays may not accurately rep resent biological function. Computational prediction tools and conservation anal ysis suggest that this variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, although additio nal studies are required to fully establish its clinical significance, the p.Arg 268His variant is likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 18, 2020	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2021

Identified in patients with SMAD3-related disorders in published literature (Wooderchak-Donahue et al., 2015; Zarate et al., 2015; Schubert et al., 2016; Camerota et al., 2019; Renner et al., 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Additionally reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 213766; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27535533, 32352226, 31569402, 30675029, 11779503, 15235019, 20101697, 27135912, 26854089, 22810696, 25944730, 10092624, 23139211, 26133393, 30833837) -

SMAD3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2024

The SMAD3 c.803G>A variant is predicted to result in the amino acid substitution p.Arg268His. This variant has been reported in multiple individuals with hereditary thoracic aortic disease and/or a clinical diagnosis of Loeys-Dietz syndrome (LDS) (Wooderchak-Donahue et al. 2015. PubMed ID: 25944730; Schubert et al. 2016. PubMed ID: 26854089; Renner et al. 2019. PubMed ID: 30675029; Camerota et al. 2019. PubMed ID: 31569402; Mariucci et al. 2020. PubMed ID: 32352226). This variant has also been reported de novo in an individual with LDS and aplastic anemia (Zha et al. 2024. PubMed ID: 38305921). In vitro studies of bone marrow mononuclear cells (BMMNCs) from this patient detected significantly decreased SMAD3 mRNA and protein expression relative to wild type (Zha et al. 2024. PubMed ID: 38305921). This variant has not been reported in the gnomAD database, indicating this variant is rare. Another missense variant at the same amino acid residue (p.Arg268Cys) has been reported in an individual with hereditary thoracic aortic disease and has been shown to be functionally damaging (Stroschein et al. 1999. PubMed ID: 10092624; Overwater et al. 2018. PubMed ID: 29907982). Taken together, the p.Arg268His variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;.;D;.;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-4.7

D;D;D;D;D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Uncertain

0.028

D;D;T;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.95

MutPred

0.95

Gain of catalytic residue at F269 (P = 0.1362);.;.;.;.;.;.;

MVP

0.99

MPC

2.7

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.83

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