9-27543384-C-T

Variant names:

• chr9-27543384-C-T
• rs3849943
• ENST00000645861.1:n.8082C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000645861.1(EMICERI):​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: EMICERI ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 29 publications found

Genes affected

EMICERI (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]

C9orf72 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive myoclonus epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000645861.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMICERI	ENST00000645861.1		n.8082C>T		non_coding_transcript_exon	Exon 2 of 2
	C9orf72	ENST00000673600.1		n.*267+4731G>A		intron	N/A	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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.833 AC: 5 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.762 AC: 31609 AN: 41496

American (AMR) AF: 0.824 AC: 12593 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2773 AN: 3470

East Asian (EAS) AF: 0.905 AC: 4690 AN: 5182

South Asian (SAS) AF: 0.824 AC: 3972 AN: 4820

European-Finnish (FIN) AF: 0.838 AC: 8869 AN: 10578

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.764 AC: 51934 AN: 68002

Other (OTH) AF: 0.776 AC: 1635 AN: 2106

Alfa AF: 0.773 Hom.: 78068

Bravo AF: 0.782

Asia WGS AF: 0.854 AC: 2968 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.47
DANN	Benign	0.74
PhyloP100		-1.4

Splicing

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

Other links and lift over

dbSNP: rs3849943; hg19: chr9-27543382;