9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-G-GAAAAAAAAA
• rs11292923
• NM_018325.5:c.1260-22_1260-14dupTTTTTTTTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_018325.5(C9orf72):​c.1260-22_1260-14dupTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0081 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (13 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 298 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-22_1260-14dupTTTTTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-22_1260-14dupTTTTTTTTT		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.1260-14_1260-13insTTTTTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 298 AN: 36768 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00862

Gnomad AMR AF: 0.00259

Gnomad ASJ AF: 0.0125

Gnomad EAS AF: 0.00343

Gnomad SAS AF: 0.00279

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00816

GnomAD4 exome AF: 0.00319 AC: 440 AN: 138112 Hom.: 13 Cov.: 0 AF XY: 0.00360 AC XY: 257 AN XY: 71368

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00513

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.000520

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.00223

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00811 AC: 298 AN: 36760 Hom.: 1 Cov.: 0 AF XY: 0.00849 AC XY: 137 AN XY: 16136

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.00258

Gnomad4 ASJ AF: 0.0125

Gnomad4 EAS AF: 0.00344

Gnomad4 SAS AF: 0.00280

Gnomad4 FIN AF: 0.00773

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00816

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;