9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_018325.5(C9orf72):​c.1260-15_1260-14delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 172,814 control chromosomes in the GnomAD database, including 156 homozygotes. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.033 (20 hom., cov: 0)
  • Exomes 𝑓: 0.081 (136 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 Benign. Variant got -9 ACMG points.

• BP6: Variant 9-27548435-GAA-G is Benign according to our data. Variant chr9-27548435-GAA-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 1215 AN: 36770 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00287

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00549

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0333

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0469

GnomAD4 exome AF: 0.0810 AC: 11020 AN: 136052 Hom.: 136 AF XY: 0.0799 AC XY: 5620 AN XY: 70354

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0599

Gnomad4 ASJ exome AF: 0.0839

Gnomad4 EAS exome AF: 0.0895

Gnomad4 SAS exome AF: 0.0587

Gnomad4 FIN exome AF: 0.0732

Gnomad4 NFE exome AF: 0.0825

Gnomad4 OTH exome AF: 0.0867

GnomAD4 genome AF: 0.0330 AC: 1214 AN: 36762 Hom.: 20 Cov.: 0 AF XY: 0.0343 AC XY: 553 AN XY: 16136

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.00551

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.0469

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;