9-27543283-T-C

Variant names:

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

Variant summary

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

The ENST00000645861.1(EMICERI):​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: EMICERI ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• Publications: 100 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=-0.94).
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMICERI	ENST00000645861.1		n.7981T>C		non_coding_transcript_exon	Exon 2 of 2
	C9orf72	ENST00000673600.1		n.*267+4832A>G		intron	N/A	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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

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) AC: 0 AN: 0

Other (OTH) AF: 1.00 AC: 2 AN: 2

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

African (AFR) AF: 0.761 AC: 31593 AN: 41492

American (AMR) AF: 0.824 AC: 12585 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 2775 AN: 3472

East Asian (EAS) AF: 0.905 AC: 4679 AN: 5172

South Asian (SAS) AF: 0.823 AC: 3972 AN: 4824

European-Finnish (FIN) AF: 0.839 AC: 8875 AN: 10582

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51935 AN: 68000

Other (OTH) AF: 0.776 AC: 1637 AN: 2110

Alfa AF: 0.771 Hom.: 194484

Bravo AF: 0.781

Asia WGS AF: 0.854 AC: 2970 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.1
DANN	Benign	0.78
PhyloP100		0.10

Splicing

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

Other links and lift over

dbSNP: rs3849942; hg19: chr9-27543281;