15-67181354-G-C

Variant names:

• chr15-67181354-G-C
• rs863223738
• NM_005902.4:c.772G>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_005902.4(SMAD3):​c.772G>C​(p.Asp258His) 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. D258A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD3 NM_005902.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.87
• Publications: 4 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 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 15-67181354-G-C is Pathogenic according to our data. Variant chr15-67181354-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 213763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005902.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	NM_005902.4	MANE Select	c.772G>C	p.Asp258His	missense	Exon 6 of 9	NP_005893.1
	SMAD3	NM_001407011.1		c.772G>C	p.Asp258His	missense	Exon 6 of 10	NP_001393940.1
	SMAD3	NM_001145103.2		c.640G>C	p.Asp214His	missense	Exon 6 of 9	NP_001138575.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD3	ENST00000327367.9	TSL:1 MANE Select	c.772G>C	p.Asp258His	missense	Exon 6 of 9	ENSP00000332973.4
	SMAD3	ENST00000439724.7	TSL:1	c.640G>C	p.Asp214His	missense	Exon 6 of 9	ENSP00000401133.3
	SMAD3	ENST00000540846.6	TSL:1	c.457G>C	p.Asp153His	missense	Exon 6 of 9	ENSP00000437757.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

May 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp258 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMAD3 protein function. This variant has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 26633542, 29650765, Invitae). ClinVar contains an entry for this variant (Variation ID: 213763). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 258 of the SMAD3 protein (p.Asp258His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine.

not provided Pathogenic:1

May 12, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); 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: 26633542, 29650765)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.90		Gain of catalytic residue at D258 (P = 0.0748)
MVP		1.0
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		0.95
gMVP		0.91
Mutation Taster		=2/98	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: rs863223738; hg19: chr15-67473692;