NM_018325.5:c.1260-18_1260-14delTTTTT

Variant names:

• chr9-27548435-GAAAAA-G
• rs11292923
• NM_018325.5:c.1260-18_1260-14delTTTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-18_1260-14delTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.0406 in 173,178 control chromosomes in the GnomAD database, including 8 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 0)
  • Exomes 𝑓: 0.051 (8 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15

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 (AMR) allele frequency at 95% confidence interval = 0.0845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-18_1260-14delTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-18_1260-14delTTTTT		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.1260-18_1260-14delTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.000489 AC: 18 AN: 36774 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000646

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00206

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000483

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0514 AC: 7015 AN: 136412 Hom.: 8 AF XY: 0.0517 AC XY: 3646 AN XY: 70508

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.0911

Gnomad4 ASJ exome AF: 0.0513

Gnomad4 EAS exome AF: 0.0858

Gnomad4 SAS exome AF: 0.0539

Gnomad4 FIN exome AF: 0.0585

Gnomad4 NFE exome AF: 0.0437

Gnomad4 OTH exome AF: 0.0551

GnomAD4 genome AF: 0.000517 AC: 19 AN: 36766 Hom.: 0 Cov.: 0 AF XY: 0.000868 AC XY: 14 AN XY: 16136

Gnomad4 AFR AF: 0.000367

Gnomad4 AMR AF: 0.000967

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00207

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000483

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;