9-27543283-T-C

Variant names:

• chr9-27543283-T-C
• rs3849942
• ENST00000645861.1:n.7981T>C

Variant summary

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

The ENST00000645861.1(ENSG00000285103):​n.7981T>C 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 152,142 control chromosomes in the GnomAD database, including 46,636 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 (46633 hom., cov: 32)
  • Exomes 𝑓: 0.88 (3 hom.)
• Consequence: ENSG00000285103 ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101

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=-0.94).
• 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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285103	ENST00000645861.1	n.7981T>C		non_coding_transcript_exon_variant	Exon 2 of 2
C9orf72	ENST00000673600.1	n.*267+4832A>G		intron_variant	Intron 11 of 11			ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118847 AN: 152016 Hom.: 46601 Cov.: 32

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.733

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.799

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.824

Gnomad FIN AF: 0.839

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.773

GnomAD4 exome AF: 0.875 AC: 7 AN: 8 Hom.: 3 Cov.: 0 AF XY: 0.833 AC XY: 5 AN XY: 6

Gnomad4 FIN exome AF: 0.833

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.782 AC: 118930 AN: 152134 Hom.: 46633 Cov.: 32 AF XY: 0.785 AC XY: 58408 AN XY: 74370

Gnomad4 AFR AF: 0.761

Gnomad4 AMR AF: 0.824

Gnomad4 ASJ AF: 0.799

Gnomad4 EAS AF: 0.905

Gnomad4 SAS AF: 0.823

Gnomad4 FIN AF: 0.839

Gnomad4 NFE AF: 0.764

Gnomad4 OTH AF: 0.776

Alfa AF: 0.766 Hom.: 91308

Bravo AF: 0.781

Asia WGS AF: 0.854 AC: 2970 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.1
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3849942; hg19: chr9-27543281;