rs863223765

chr15-67164966-G-Achr15-67164966-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_005902.4(SMAD3):c.278G>A(p.Arg93Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.77

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_005902.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMAD3
• PP5: Variant 15-67164966-G-A is Pathogenic according to our data. Variant chr15-67164966-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213800.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.278G>A	p.Arg93Gln	missense_variant	2/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.278G>A	p.Arg93Gln	missense_variant	2/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 93 of the SMAD3 protein (p.Arg93Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related disease (PMID: 29543232; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213800). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 25, 2022	- -

Aneurysm-osteoarthritis syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Cologne University	Nov 03, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 04, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 11, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213800; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23139211, 29543232) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Pathogenic	-5.0	D
Vest4		0.28
MVP		0.93
ClinPred		1.0	D
GERP RS		4.4

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: rs863223765; hg19: chr15-67457304; COSMIC: COSV59280349; COSMIC: COSV59280349;