rs774359
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_145005.7(C9orf72):c.*530A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 179,578 control chromosomes in the GnomAD database, including 5,012 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.23 ( 4044 hom., cov: 32)
Exomes 𝑓: 0.26 ( 968 hom. )
Consequence
C9orf72
NM_145005.7 3_prime_UTR
NM_145005.7 3_prime_UTR
Scores
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.296
Genes affected
C9orf72 (HGNC:28337): (C9orf72-SMCR8 complex subunit) The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
C9orf72 | NM_018325.5 | c.665+534A>G | intron_variant | ENST00000380003.8 | NP_060795.1 | |||
C9orf72 | NM_145005.7 | c.*530A>G | 3_prime_UTR_variant | 5/5 | NP_659442.2 | |||
C9orf72 | NM_001256054.3 | c.665+534A>G | intron_variant | NP_001242983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
C9orf72 | ENST00000380003.8 | c.665+534A>G | intron_variant | 1 | NM_018325.5 | ENSP00000369339.3 |
Frequencies
GnomAD3 genomes AF: 0.226 AC: 34286AN: 151818Hom.: 4036 Cov.: 32
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GnomAD4 exome AF: 0.264 AC: 7298AN: 27642Hom.: 968 Cov.: 4 AF XY: 0.262 AC XY: 3552AN XY: 13564
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GnomAD4 genome AF: 0.226 AC: 34320AN: 151936Hom.: 4044 Cov.: 32 AF XY: 0.222 AC XY: 16451AN XY: 74260
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ClinVar
Not reported inComputational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at