rs17769217

Positions:

• chr9-27543533-C-G
• chr9-27543533-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000645861.1(ENSG00000285103):​n.8231C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 132,914 control chromosomes in the GnomAD database, including 883 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (883 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000285103 ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24

Genes affected

ENSG00000285103 (HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.27543533C>G		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000285103	ENST00000645861.1	n.8231C>G		non_coding_transcript_exon_variant	2/2
C9orf72	ENST00000673600.1	n.*267+4582G>C		intron_variant				ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 14608 AN: 132820 Hom.: 883 Cov.: 33

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.0998

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000990

Gnomad SAS AF: 0.0910

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.120

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.110 AC: 14606 AN: 132914 Hom.: 883 Cov.: 33 AF XY: 0.113 AC XY: 7222 AN XY: 64104

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.0996

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.000744

Gnomad4 SAS AF: 0.0909

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.119

Alfa AF: 0.0565 Hom.: 57

Bravo AF: 0.0872

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17769217; hg19: chr9-27543531;