rs3861016

Variant names:

• chr9-27543043-T-G
• rs3861016
• ENST00000645861.1:n.7741T>G

Variant summary

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

The ENST00000645861.1(EMICERI):​n.7741T>G 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 0.0639 in 152,308 control chromosomes in the GnomAD database, including 461 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 0.064 (461 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: EMICERI ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.680
• Publications: 2 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 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
EMICERI	ENST00000645861.1	n.7741T>G		non_coding_transcript_exon_variant	Exon 2 of 2
C9orf72	ENST00000673600.1	n.*267+5072A>C		intron_variant	Intron 11 of 11			ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9728 AN: 152190 Hom.: 460 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0666

Gnomad OTH AF: 0.0756

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

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0639 AC: 9726 AN: 152308 Hom.: 461 Cov.: 33 AF XY: 0.0674 AC XY: 5023 AN XY: 74478

African (AFR) AF: 0.0144 AC: 597 AN: 41574

American (AMR) AF: 0.118 AC: 1808 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3472

East Asian (EAS) AF: 0.149 AC: 771 AN: 5180

South Asian (SAS) AF: 0.142 AC: 684 AN: 4830

European-Finnish (FIN) AF: 0.0707 AC: 750 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0666 AC: 4529 AN: 68024

Other (OTH) AF: 0.0748 AC: 158 AN: 2112

Alfa AF: 0.0628 Hom.: 50

Bravo AF: 0.0648

Asia WGS AF: 0.129 AC: 448 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.0
DANN	Benign	0.85
PhyloP100		0.68

Splicing

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

Other links and lift over

dbSNP: rs3861016; hg19: chr9-27543041;