chr9-27541043-C-T

Variant names:

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

Variant summary

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

The ENST00000645861.1(EMICERI):​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: EMICERI ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 12 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMICERI	ENST00000645861.1		n.5741C>T		non_coding_transcript_exon	Exon 2 of 2
	C9orf72	ENST00000673600.1		n.*268-4757G>A		intron	N/A	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

African (AFR) AF: 0.00 AC: 0 AN: 4

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: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.500 AC: 9 AN: 18

Other (OTH) AF: 0.500 AC: 5 AN: 10

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

African (AFR) AF: 0.134 AC: 5577 AN: 41492

American (AMR) AF: 0.471 AC: 7197 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2169 AN: 3470

East Asian (EAS) AF: 0.594 AC: 3062 AN: 5158

South Asian (SAS) AF: 0.483 AC: 2333 AN: 4830

European-Finnish (FIN) AF: 0.509 AC: 5361 AN: 10540

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.488 AC: 33123 AN: 67944

Other (OTH) AF: 0.419 AC: 884 AN: 2112

Alfa AF: 0.442 Hom.: 5240

Bravo AF: 0.381

Asia WGS AF: 0.465 AC: 1617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.5
DANN	Benign	0.75
PhyloP100		-0.028

Splicing

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

Other links and lift over

dbSNP: rs7469146; hg19: chr9-27541041;