9-27542263-C-T

Position:

• chr9-27542263-C-T

Variant summary

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

The ENST00000645861.1(ENSG00000285103):​n.6961C>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 0.427 in 151,964 control chromosomes in the GnomAD database, including 16,338 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 0.43 (16338 hom., cov: 32)
  • 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: -1.05

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 = 0.579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.27542263C>T		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000285103	ENST00000645861.1	n.6961C>T		non_coding_transcript_exon_variant	2/2
C9orf72	ENST00000673600.1	n.*267+5852G>A		intron_variant				ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64866 AN: 151846 Hom.: 16343 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.449

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

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.427 AC: 64852 AN: 151964 Hom.: 16338 Cov.: 32 AF XY: 0.433 AC XY: 32126 AN XY: 74260

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.640

Gnomad4 EAS AF: 0.597

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.587

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.444

Alfa AF: 0.515 Hom.: 41366

Bravo AF: 0.407

Asia WGS AF: 0.473 AC: 1644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.76
DANN	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10812611; hg19: chr9-27542261; COSMIC: COSV66163349;