SMAD5

protein-coding

SMAD family member 5, the group of SMAD family

Gene summary

The protein encoded by this gene is involved in the transforming growth factor beta signaling pathway that results in an inhibition of the proliferation of hematopoietic progenitor cells. The encoded protein is activated by bone morphogenetic proteins type 1 receptor kinase, and may be involved in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Previous symbols:

MADH5

MANE transcript

NM_005903.7

Inheritance

—

ClinVar variants

U:29

Top phenotype

Congenital heart disease

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr5:136,132,845-136,188,747

External References & Databases

Ensembl (ENSG00000113658)

Transcript & Mutation Effects

hg38 • Region Span ~55.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMAD5 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 22

Congenital heart diseaseTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005903.7. 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			1 clinvar			1
missense			26 clinvar			26
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)						0
Total	0	0	29	0	0	29

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005903.7	RefSeq	NP_005894.3	6	MANE Select
ENST00000545279.6	Ensembl	ENSP00000441954.2	6	MANE Select
NM_001001419.3	RefSeq	NP_001001419.1	6	Standard
NM_001001420.3	RefSeq	NP_001001420.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
smad5	Danio rerio	Structure: erythroid lineage cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

smad5

Danio rerio

Structure: erythroid lineage cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-beta signaling pathway - Homo sapiens (human)
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
TGF-Core
Differentiation of white and brown adipocyte
BMP2-WNT4-FOXO1 Pathway in Human Primary Endometrial Stromal Cell Differentiation

Biological Process

negative regulation of transcription by RNA polymerase II
ureteric bud development
Mullerian duct regression
osteoblast fate commitment
protein phosphorylation

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
protein binding
DEAD/H-box RNA helicase binding
transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000545279
Coding exons: 7
Length: 55902
Individuals with no LoFs: 395
Homozygous LoFs: 124736
Heterozygous LoFs: 0
Defined: 125131
p: 0.944

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.00	117	251	0.467	0.0000128	3086
Missense (PolyPhen)		23	91.326	0.25184		1129
Synonymous	0.636	78	85.5	0.913	0.00000435	844
Loss of Function	4.01	0	18.7	0.00	9.61e-7	231

Population LoF Frequency

Population	CAF	p-value	Status
African	1.0	0.95	notable
Latino/Admixed American	1.0	0.95	notable
Ashkenazi Jewish	1.0	0.95	notable
East Asian	1.0	0.96	notable
Finnish	1.0	0.95	notable
European (Non-Finnish)	1.0	0.94	notable
South Asian	1.0	0.93	notable
Other	1.0	0.93	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD5 is a receptor-regulated SMAD (R-SMAD).;

Recessive Scores

pRec: 0.240

Essentials

Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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