9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-G-GAAAAAAA
• rs11292923
• NM_018325.5:c.1260-20_1260-14dupTTTTTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-20_1260-14dupTTTTTTT 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 0.0042 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00094 (2 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 155 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-20_1260-14dupTTTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-20_1260-14dupTTTTTTT		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_1260-13insTTTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 156 AN: 36766 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00575

Gnomad AMR AF: 0.000646

Gnomad ASJ AF: 0.00368

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00279

Gnomad FIN AF: 0.00258

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.00575

Gnomad OTH AF: 0.00612

GnomAD4 exome AF: 0.000941 AC: 130 AN: 138108 Hom.: 2 Cov.: 0 AF XY: 0.00102 AC XY: 73 AN XY: 71364

Gnomad4 AFR exome AF: 0.000323

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.000537

Gnomad4 EAS exome AF: 0.00104

Gnomad4 SAS exome AF: 0.00239

Gnomad4 FIN exome AF: 0.000620

Gnomad4 NFE exome AF: 0.000767

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00422 AC: 155 AN: 36758 Hom.: 1 Cov.: 0 AF XY: 0.00335 AC XY: 54 AN XY: 16134

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.000645

Gnomad4 ASJ AF: 0.00368

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00280

Gnomad4 FIN AF: 0.00258

Gnomad4 NFE AF: 0.00575

Gnomad4 OTH AF: 0.00612

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;