ASCC1

protein-coding

activating signal cointegrator 1 complex subunit 1, the group of Activating signal cointegrator 1 complex

Gene summary

This gene encodes a subunit of the activating signal cointegrator 1 (ASC-1) complex. The ASC-1 complex is a transcriptional coactivator that plays an important role in gene transactivation by multiple transcription factors including activating protein 1 (AP-1), nuclear factor kappa-B (NF-kB) and serum response factor (SRF). The encoded protein contains an N-terminal KH-type RNA-binding motif which is required for AP-1 transactivation by the ASC-1 complex. Mutations in this gene are associated with Barrett esophagus and esophageal adenocarcinoma. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

MANE transcript

NM_001198800.3

Inheritance

AR, AD

ClinVar variants

P:26U:78B:48

Top phenotype

Barrett esophagus/Esophageal adenocarcinoma

gnomAD constraint

pLI —, LoF o/e 0.92

Max pathogenic AF

—

Genomic locus

chr10:72,096,032-72,217,134

External References & Databases

Ensembl (ENSG00000138303)

Transcript & Mutation Effects

hg38 • Region Span ~121.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinal muscular atrophy with congenital bone fractures 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014807

Submitter: G2P

spinal muscular atrophy with congenital bone fractures 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014807

Submitter: PanelApp Australia

spinal muscular atrophy with congenital bone fractures 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014807

Submitter: Illumina

spinal muscular atrophy with congenital bone fractures 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014807

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Barrett esophagus/Esophageal adenocarcinomaAD

Manifestation: Gastrointestinal; Musculoskeletal; Neurologic; Oncologic

Intervention: Gastrointestinal; Oncologic

Rationale: Awareness of disease risk may allow surveillance, preventive measures (eg, related to Barrett esophagus) and early treatment of malignancy, which may reduce morbidity and mortality

Refs: 21791690; 26924529; 28218388; 30327447

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASCC1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 172

Inborn genetic diseasesTotal: 45

Spinal muscular atrophy with congenital bone fractures 2Total: 21

ASCC1-related disorderTotal: 16

not specifiedTotal: 14

Barrett esophagusTotal: 2

BARRETT ESOPHAGUS/ESOPHAGEAL ADENOCARCINOMATotal: 1

Fetal akinesia deformation sequence 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001198800.3. 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	39 clinvar	1 clinvar	41
missense		1 clinvar	72 clinvar	7 clinvar	1 clinvar	81
nonsense	10 clinvar	3 clinvar	1 clinvar			14
start loss						0
frameshift	3 clinvar	3 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar	3 clinvar			9
Total	14	12	78	46	2	152

Highest pathogenic variant AF is 0.00003532592

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 88 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001198800.3	RefSeq	NP_001185729.1	9	MANE Select
ENST00000672957.1	Ensembl	ENSP00000500935.1	9	MANE Select
NM_001198798.2	RefSeq	NP_001185727.1	9	Standard
NM_001198799.3	RefSeq	NP_001185728.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ascc1	Danio rerio	Structure: motor neuron Quality: branchiness abnormal

Gene / Model

Organism

Observed Phenotype

ascc1

Danio rerio

Structure: motor neuron

Quality: branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

DNA Repair
ALKBH3 mediated reversal of alkylation damage
Reversal of alkylation damage by DNA dioxygenases
DNA Damage Reversal

Biological Process

DNA dealkylation involved in DNA repair
regulation of transcription, DNA-templated

Molecular Function

RNA binding
protein binding

Cellular Component

nucleus
nucleoplasm
transcription factor complex
nuclear speck
neuromuscular junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342444
Coding exons: 11
Length: 120615
Individuals with no LoFs: 125685
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125748
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.838	173	207	0.836	0.0000107	2643
Missense (PolyPhen)		42	58.997	0.7119		722
Synonymous	-0.146	75	73.4	1.02	0.00000378	729
Loss of Function	0.352	22	23.9	0.922	0.00000140	271

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00026	0.00026	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in DNA damage repair as component of the ASCC complex (PubMed:29997253). Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation (PubMed:12077347). In cells responding to gastrin-activated paracrine signals, it is involved in the induction of SERPINB2 expression by gastrin. May also play a role in the development of neuromuscular junction. {ECO:0000269|PubMed:12077347, ECO:0000269|PubMed:19074642, ECO:0000269|PubMed:26924529, ECO:0000269|PubMed:29997253}.;
Disease: DISEASE: Spinal muscular atrophy with congenital bone fractures 2 (SMABF2) [MIM:616867]: An autosomal recessive neuromuscular disorder characterized by prenatal-onset spinal muscular atrophy, multiple congenital contractures consistent with arthrogryposis multiplex congenita, respiratory distress, and congenital bone fractures. {ECO:0000269|PubMed:26924529}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0761

Intolerance Scores

RVIS EVS: 0.8
RVIS percentile EVS: 87.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.912

Gene Damage Prediction

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