rs753324947
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2
The NM_001198800.3(ASCC1):c.157_158insG(p.Glu53GlyfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
ASCC1
NM_001198800.3 frameshift
NM_001198800.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.64
Genes affected
ASCC1 (HGNC:24268): (activating signal cointegrator 1 complex subunit 1) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 10-72210786-T-TC is Pathogenic according to our data. Variant chr10-72210786-T-TC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
?
High AC in GnomAdExome at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASCC1 | NM_001198800.3 | c.157_158insG | p.Glu53GlyfsTer19 | frameshift_variant | 3/10 | ENST00000672957.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASCC1 | ENST00000672957.1 | c.157_158insG | p.Glu53GlyfsTer19 | frameshift_variant | 3/10 | NM_001198800.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152054Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251406Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135894
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GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727228
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spinal muscular atrophy with congenital bone fractures 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 06, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 28, 2021 | - - |
See cases Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Sep 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Apr 26, 2021 | PVS1_very strong;PM3_supporting;PP5_supporting - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 04, 2023 | This premature translational stop signal has been observed in individuals with clinical features of ASCC1-related conditions (PMID: 26924529, 28218388, 30327447). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224639). This variant is present in population databases (rs753324947, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Glu53Glyfs*19) in the ASCC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASCC1 are known to be pathogenic (PMID: 30327447). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at