9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAA

Variant names:

• chr9-27548435-GAAAAAAAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-25_1260-14delTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_018325.5(C9orf72):​c.1260-25_1260-14delTTTTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.0019 in 174,882 control chromosomes in the GnomAD database, including 7 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00076 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0022 (5 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.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0022 (304/138116) while in subpopulation MID AF= 0.0483 (26/538). AF 95% confidence interval is 0.0339. There are 5 homozygotes in gnomad4_exome. There are 158 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-25_1260-14delTTTTTTTTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-25_1260-14delTTTTTTTTTTTT		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.1260-25_1260-14delTTTTTTTTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.000761 AC: 28 AN: 36774 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00355

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0345

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00220 AC: 304 AN: 138116 Hom.: 5 AF XY: 0.00221 AC XY: 158 AN XY: 71376

Gnomad4 AFR exome AF: 0.00581

Gnomad4 AMR exome AF: 0.00442

Gnomad4 ASJ exome AF: 0.000805

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000252

Gnomad4 FIN exome AF: 0.000248

Gnomad4 NFE exome AF: 0.00233

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.000762 AC: 28 AN: 36766 Hom.: 2 Cov.: 0 AF XY: 0.000868 AC XY: 14 AN XY: 16134

Gnomad4 AFR AF: 0.000122

Gnomad4 AMR AF: 0.00355

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00140

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000677

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;