9-27543384-C-T

Position:

• chr9-27543384-C-T

Variant summary

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

The ENST00000645861.1(ENSG00000285103):​n.8082C>T 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 0.782 in 152,160 control chromosomes in the GnomAD database, including 46,652 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 0.78 (46648 hom., cov: 32)
  • Exomes 𝑓: 0.83 (4 hom.)
• Consequence: ENSG00000285103 ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.27543384C>T		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000285103	ENST00000645861.1	n.8082C>T		non_coding_transcript_exon_variant	2/2
C9orf72	ENST00000673600.1	n.*267+4731G>A		intron_variant				ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118871 AN: 152030 Hom.: 46616 Cov.: 32

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.774

GnomAD4 exome AF: 0.833 AC: 10 AN: 12 Hom.: 4 Cov.: 0 AF XY: 0.800 AC XY: 8 AN XY: 10

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.750

GnomAD4 genome AF: 0.782 AC: 118954 AN: 152148 Hom.: 46648 Cov.: 32 AF XY: 0.785 AC XY: 58420 AN XY: 74386

Gnomad4 AFR AF: 0.762

Gnomad4 AMR AF: 0.824

Gnomad4 ASJ AF: 0.799

Gnomad4 EAS AF: 0.905

Gnomad4 SAS AF: 0.824

Gnomad4 FIN AF: 0.838

Gnomad4 NFE AF: 0.764

Gnomad4 OTH AF: 0.776

Alfa AF: 0.770 Hom.: 14112

Bravo AF: 0.782

Asia WGS AF: 0.854 AC: 2968 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.47
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3849943; hg19: chr9-27543382;