NM_018325.5:c.1260-17_1260-14delTTTT

Variant names:

• chr9-27548435-GAAAA-G
• rs11292923
• NM_018325.5:c.1260-17_1260-14delTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_018325.5(C9orf72):​c.1260-17_1260-14delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 136,160 control chromosomes in the GnomAD database, including 207 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.039 (76 hom., cov: 0)
  • Exomes 𝑓: 0.17 (207 hom.)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.477

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-17_1260-14delTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-17_1260-14delTTTT		intron_variant	Intron 10 of 10		NP_001242983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.1260-17_1260-14delTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 1435 AN: 36812 Hom.: 74 Cov.: 0

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0460

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0169

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0531

GnomAD4 exome AF: 0.170 AC: 23102 AN: 136160 Hom.: 207 AF XY: 0.168 AC XY: 11848 AN XY: 70324

Gnomad4 AFR exome AF: 0.0765

Gnomad4 AMR exome AF: 0.221

Gnomad4 ASJ exome AF: 0.183

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0391 AC: 1438 AN: 36804 Hom.: 76 Cov.: 0 AF XY: 0.0442 AC XY: 715 AN XY: 16160

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0169

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0974

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.0531

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11292923; hg19: chr9-27548433;