15-67187457-C-T

Variant names:

• chr15-67187457-C-T
• rs757106110
• NM_005902.4:c.1102C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005902.4(SMAD3):​c.1102C>T​(p.Arg368*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.53

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-67187457-C-T is Pathogenic according to our data. Variant chr15-67187457-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 420088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-67187457-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.1102C>T	p.Arg368*	stop_gained	Exon 8 of 9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.1102C>T	p.Arg368*	stop_gained	Exon 8 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Dec 14, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R368* pathogenic mutation (also known as c.1102C>T), located in coding exon 8 of the SMAD3 gene, results from a C to T substitution at nucleotide position 1102. This changes the amino acid from an arginine to a stop codon within coding exon 8. This alteration is located in the MH2 domain, which is involved in the oligomerization of the SMAD3/SMAD4 complex (Chacko BM et al Nat Struct Biol. 2001;8(3):248-53). This alteration has been described in a Loeys-Dietz syndrome type 3 cohort (Aubart M et al. PLoS ONE. 2014;9:e96387). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Sep 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg368*) in the SMAD3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD3 are known to be pathogenic (PMID: 21778426, 24804794). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with SMAD3-related conditions (PMID: 24804794). ClinVar contains an entry for this variant (Variation ID: 420088). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 58 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28185953, 26221609, 30787465, 29392890, 31447099, 30118648, 34150014, 24804794, 30661052, 35031499, 35943490) -

Aneurysm-osteoarthritis syndrome Pathogenic:1

Aug 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1102C>T (p.Arg368*) variant in the SMAD3 gene is located in exon 8 (of 9) and is predicted to create a premature stop codon. This variant is predicted to result in an absent or aberrant protein product. This variant has been reported in individuals and families with familial thoracic aortic aneurysm and dissection (FTAAD), Loeys-Dietz syndrome type III or related disorders (PMID: 24804794, 29392890, 30661052, 34150014, 35031499). Truncating variants in SMAD3 are known to be pathogenic (PMID: 26333736, 32597575). ClinVar contains an entry for this variant (ID: 420088). Other stopgain or frameshifting variants downstream of this variant in the same exon have been reported to be pathogenic for FTAAD in ClinVar (IDs: 1730647, 582880, 1453411). This variant is absent in the general population database gnomAD (v2.1.1). Therefore, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.97
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs757106110; hg19: chr15-67479795; COSMIC: COSV59282338; COSMIC: COSV59282338;