SMAD3

protein-coding

SMAD family member 3, the group of SMAD family

Gene summary

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]

Previous symbols:

MADH3

MANE transcript

NM_005902.4

Inheritance

ClinVar variants

P:248U:464B:261

Top phenotype

Loeys-Dietz syndrome, type 3

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr15:67,063,763-67,195,173

External References & Databases

Ensembl (ENSG00000166949)

Transcript & Mutation Effects

hg38 • Region Span ~131.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial thoracic aortic aneurysm and aortic dissectionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Orphanet

aneurysm-osteoarthritis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013426

Submitter: Genomics England PanelApp

aneurysm-osteoarthritis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013426

Submitter: Orphanet

aneurysm-osteoarthritis syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013426

Submitter: Labcorp Genetics (formerly Invitae)

aneurysm-osteoarthritis syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013426

Submitter: G2P

Clinical Genomic Database (CGD)

Loeys-Dietz syndrome, type 3AD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal

Intervention: Cardiovascular

Rationale: Preventive measures and medical management may be helpful to help decrease morbidity, especially related to cardiovascular complications, which can result in sequelae such as sudden death, primarily due to aortic dissection and/or rupture

Refs: 21217753; 21778426; 22167769

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMAD3 variants in ClinVar

21 Conditions Cataloged

Familial thoracic aortic aneurysm and aortic dissectionTotal: 949

Aneurysm-osteoarthritis syndromeTotal: 314

not providedTotal: 306

not specifiedTotal: 107

SMAD3-related disorderTotal: 67

Ehlers-Danlos syndromeTotal: 16

Cardiovascular phenotypeTotal: 15

Loeys-Dietz syndromeTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005902.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	249 clinvar	3 clinvar	256
missense	8 clinvar	69 clinvar	451 clinvar	9 clinvar		537
nonsense	27 clinvar	15 clinvar	3 clinvar			45
start loss	1 clinvar	4 clinvar				5
frameshift	62 clinvar	35 clinvar	1 clinvar			98
splice donor/acceptor (+/-2bp)	6 clinvar	21 clinvar	5 clinvar			32
Total	104	144	464	258	3	973

Highest pathogenic variant AF is 0.0000065747086

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005902.4	RefSeq	NP_005893.1	9	MANE Select
ENST00000327367.9	Ensembl	ENSP00000332973.4	9	MANE Select
NM_001145102.2	RefSeq	NP_001138574.1	8	Standard
NM_001145103.2	RefSeq	NP_001138575.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
smad3b	Danio rerio	Structure: neuron Quality: degenerate abnormal

Gene / Model

Organism

Observed Phenotype

smad3b

Danio rerio

Structure: neuron

Quality: degenerate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Chronic myeloid leukemia - Homo sapiens (human)
Gastric cancer - Homo sapiens (human)
Relaxin signaling pathway - Homo sapiens (human)
TGF-beta signaling pathway - Homo sapiens (human)
Adherens junction - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
ureteric bud development
response to hypoxia
in utero embryonic development
mesoderm formation

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
proximal promoter sequence-specific DNA binding
RNA polymerase II activating transcription factor binding
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nuclear chromatin
nucleus
nuclear inner membrane
nucleoplasm
transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000327367
Coding exons: 9
Length: 131433
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.48	97	253	0.384	0.0000164	2791
Missense (PolyPhen)		13	86.992	0.14944		1006
Synonymous	-0.958	119	106	1.12	0.00000770	812
Loss of Function	3.66	4	22.9	0.175	0.00000118	238

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF- mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000269|PubMed:10995748, ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:15588252, ECO:0000269|PubMed:16156666, ECO:0000269|PubMed:16751101, ECO:0000269|PubMed:16862174, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:19218245, ECO:0000269|PubMed:19289081, ECO:0000269|PubMed:9732876, ECO:0000269|PubMed:9892009}.;
Disease: DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:16959974}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Loeys-Dietz syndrome 3 (LDS3) [MIM:613795]: An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. {ECO:0000269|PubMed:21217753, ECO:0000269|PubMed:21778426}. Note=The disease is caused by mutations affecting the gene represented in this entry. SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource. {ECO:0000269|PubMed:21778426}.;

Recessive Scores

pRec: 0.777

Intolerance Scores

LoFtool: 0.0685
RVIS EVS: -0.34
RVIS percentile EVS: 30.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium