9-27541043-C-T

Variant names:

• chr9-27541043-C-T
• rs7469146
• ENST00000645861.1:n.5741C>T

Variant summary

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

The ENST00000645861.1(ENSG00000285103):​n.5741C>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 0.396 in 152,072 control chromosomes in the GnomAD database, including 14,146 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 0.40 (14143 hom., cov: 32)
  • Exomes 𝑓: 0.42 (3 hom.)
• Consequence: ENSG00000285103 ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280

Genes affected

ENSG00000285103 (HGNC:53656): (EQTN MOB3B IFNK C9orf72 enhancer RNA I)

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285103	ENST00000645861.1	n.5741C>T		non_coding_transcript_exon_variant	Exon 2 of 2
C9orf72	ENST00000673600.1	n.*268-4757G>A		intron_variant	Intron 11 of 11			ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60280 AN: 151916 Hom.: 14145 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.423

GnomAD4 exome AF: 0.421 AC: 16 AN: 38 Hom.: 3 Cov.: 0 AF XY: 0.409 AC XY: 9 AN XY: 22

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.396 AC: 60269 AN: 152034 Hom.: 14143 Cov.: 32 AF XY: 0.402 AC XY: 29879 AN XY: 74304

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.471

Gnomad4 ASJ AF: 0.625

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.483

Gnomad4 FIN AF: 0.509

Gnomad4 NFE AF: 0.488

Gnomad4 OTH AF: 0.419

Alfa AF: 0.442 Hom.: 2735

Bravo AF: 0.381

Asia WGS AF: 0.465 AC: 1617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.5
DANN	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7469146; hg19: chr9-27541041;