SMG9

protein-coding

SMG9 nonsense mediated mRNA decay factor, the group of SMG1 complex

Gene summary

This gene encodes a regulatory subunit of the SMG1 complex, which plays a critical role in nonsense-mediated mRNA decay (NMD). Binding of the encoded protein to the SMG1 complex kinase scaffold protein results in the inhibition of its kinase activity. Mutations in this gene cause a multiple congenital anomaly syndrome in human patients, characterized by brain malformation, congenital heart disease and other features. [provided by RefSeq, Jul 2016]

Previous symbols:

C19orf61

MANE transcript

NM_019108.4

Inheritance

ClinVar variants

P:20U:83B:28

Top phenotype

Heart and brain malformation syndrome; Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr19:43,727,983-43,754,962

External References & Databases

Ensembl (ENSG00000105771)

Transcript & Mutation Effects

hg38 • Region Span ~27.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

heart and brain malformation syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014833

Submitter: Labcorp Genetics (formerly Invitae)

heart and brain malformation syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014833

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Heart and brain malformation syndrome; Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomaliesAR

Manifestation: Cardiovascular; Craniofacial; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 27018474; 35087184

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMG9 variants in ClinVar

13 Conditions Cataloged

Inborn genetic diseasesTotal: 73

not providedTotal: 41

SMG9-related disorderTotal: 14

Heart and brain malformation syndromeTotal: 12

Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomaliesTotal: 8

not specifiedTotal: 6

Global developmental delayTotal: 2

Brainstem dysplasiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019108.4. 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			1 clinvar	22 clinvar	2 clinvar	25
missense	2 clinvar	1 clinvar	79 clinvar	4 clinvar		86
nonsense	3 clinvar	4 clinvar				7
start loss						0
frameshift	3 clinvar	6 clinvar	2 clinvar			11
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	8	12	83	26	2	131

Highest pathogenic variant AF is 0.00007125296

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019108.4	RefSeq	NP_061981.2	13	MANE Select
ENST00000270066.11	Ensembl	ENSP00000270066.6	13	MANE Select
ENST00000596714.1	Ensembl	ENSP00000470541.1	3	Standard
ENST00000597586.5	Ensembl	ENSP00000472684.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of RNA
Nonsense-Mediated Decay (NMD)
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

Biological Process

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
eye development
brain development
heart development

Molecular Function

protein binding
identical protein binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000270066
Coding exons: 13
Length: 23842
Individuals with no LoFs: 125672
Homozygous LoFs: 0
Heterozygous LoFs: 76
Defined: 125748
p: 0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.60	240	320	0.749	0.0000189	3369
Missense (PolyPhen)		54	84.374	0.64001		835
Synonymous	0.592	113	121	0.932	0.00000699	1058
Loss of Function	1.13	23	29.7	0.775	0.00000164	304

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00031	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00049	0.00049	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00028	0.00028	rare
South Asian	0.00026	0.00026	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons (PubMed:19417104). Is recruited by release factors to stalled ribosomes together with SMG1 and SMG8 (forming the SMG1C protein kinase complex) and, in the SMG1C complex, is required for the efficient association between SMG1 and SMG8 (PubMed:19417104). Plays a role in brain, heart, and eye development (By similarity). {ECO:0000250|UniProtKB:Q9DB90, ECO:0000269|PubMed:19417104}.;
Disease: DISEASE: Heart and brain malformation syndrome (HBMS) [MIM:616920]: An autosomal recessive syndrome characterized by multiple congenital anomalies such as cardiac defects, brain malformations, including cerebellar vermis hypoplasia, hypoplastic corpus callosum and Dandy-Walker malformation, profoundly delayed psychomotor development, microphthalmia, and facial dysmorphism. {ECO:0000269|PubMed:27018474}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: -0.76
RVIS percentile EVS: 13.45

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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