rs863223737

chr15-67181315-G-Achr15-67181315-G-C

Variant summary

Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_005902.4(SMAD3):c.733G>A(p.Gly245Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G245E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.87

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 Pathogenic. Variant got 25 ACMG points.

• PS1: Transcript NM_005902.4 (SMAD3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 520179
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005902.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMAD3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 15-67181315-G-A is Pathogenic according to our data. Variant chr15-67181315-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67181315-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-67181315-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD3	NM_005902.4	c.733G>A	p.Gly245Arg	missense_variant	6/9	ENST00000327367.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD3	ENST00000327367.9	c.733G>A	p.Gly245Arg	missense_variant	6/9	1	NM_005902.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727190

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 13, 2022	The p.G245R variant (also known as c.733G>A), located in coding exon 6 of the SMAD3 gene, results from a G to A substitution at nucleotide position 733. The glycine at codon 245 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with SMAD3-related phenotypes and has been reported to segregate with disease in a small number of affected relatives (Hostetler EM et al. J. Med. Genet., 2019 Apr;56:252-260; Ambry internal data; GeneDx pers. comm.; Invitae pers. comm.). Internal structural analysis indicates that this variant causes a significant decrease in SMAD3 structural stability (Qin BY et al. Genes Dev. 2002 Aug;16(15):1950-63; Ambry internal data). A different alteration located at the same position, resulting in the same protein change, c.733G>C (p.G245R), has been reported in an individual with aortic root dilation (Arroyave J et al. Cardiol Young, 2018;28:765-767). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 245 of the SMAD3 protein (p.Gly245Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 24804794, 29444731; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213762). 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.Gly245 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Reported in association with Loeys-Dietz syndrome (LDS) or thoracic aortic aneurysm and dissection (TAAD) in published literature and in patients referred for genetic testing at GeneDx (Ripoll-Vera et al., 2021; Hostetler et al., 2019; Aubart et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26221609, 28185953, 35830949, 30661052, 29444731, 32917565, 24804794) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	34
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	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.7	D;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.99
MutPred		0.93		Gain of sheet (P = 0.1539);.;.;.;.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.90

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: rs863223737; hg19: chr15-67473653; COSMIC: COSV59280993; COSMIC: COSV59280993;