9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-G-GAA
• rs11292923
• NM_018325.5:c.1260-15_1260-14dupTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-15_1260-14dupTT 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 0.0029 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0041 (0 hom.)
  • Failed GnomAD Quality Control
• 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 GnomAdExome4 at 570 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-15_1260-14dupTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-15_1260-14dupTT		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_1260-13insTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 106 AN: 36774 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00226

Gnomad ASJ AF: 0.000735

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.00140

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00414 AC: 570 AN: 137830 Hom.: 0 Cov.: 0 AF XY: 0.00452 AC XY: 322 AN XY: 71226

Gnomad4 AFR exome AF: 0.00614

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00565

Gnomad4 EAS exome AF: 0.00179

Gnomad4 SAS exome AF: 0.00416

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.00445

Gnomad4 OTH exome AF: 0.00506

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00288 AC: 106 AN: 36766 Hom.: 3 Cov.: 0 AF XY: 0.00229 AC XY: 37 AN XY: 16136

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.00226

Gnomad4 ASJ AF: 0.000735

Gnomad4 EAS AF: 0.00138

Gnomad4 SAS AF: 0.00140

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00295

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;