15-67181364-C-T

Variant names:

• chr15-67181364-C-T
• rs387906851
• NM_005902.4:c.782C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_005902.4(SMAD3):​c.782C>T​(p.Thr261Ile) 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. 13/22 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. T261A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.80
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• aneurysm-osteoarthritis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005902.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 15-67181364-C-T is Pathogenic according to our data. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-67181364-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 30308.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD3	NM_005902.4	c.782C>T	p.Thr261Ile	missense_variant	Exon 6 of 9	ENST00000327367.9	NP_005893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD3	ENST00000327367.9	c.782C>T	p.Thr261Ile	missense_variant	Exon 6 of 9	1	NM_005902.4	ENSP00000332973.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.000433 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aneurysm-osteoarthritis syndrome Pathogenic:1

Feb 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;.;.;D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.;.;.;.;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.97
MutPred		0.82		Loss of disorder (P = 0.0215);.;.;.;.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.80
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906851; hg19: chr15-67473702; COSMIC: COSV59282394;