9-27536399-C-T

Variant names:

• chr9-27536399-C-T
• rs2814707
• ENST00000645861.1:n.1097C>T

Variant summary

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

The ENST00000645861.1(EMICERI):​n.1097C>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 0.212 in 152,136 control chromosomes in the GnomAD database, including 3,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.21 (3634 hom., cov: 32)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: EMICERI ENST00000645861.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.516
• Publications: 69 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=-0.74).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.235 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.1097C>T		non_coding_transcript_exon_variant	Exon 2 of 2
C9orf72	ENST00000673600.1	n.*268-113G>A		intron_variant	Intron 11 of 11			ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32292 AN: 152002 Hom.: 3626 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0669

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.0625 AC: 1 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12

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: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.100 AC: 1 AN: 10

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.212 AC: 32316 AN: 152120 Hom.: 3634 Cov.: 32 AF XY: 0.209 AC XY: 15538 AN XY: 74364

African (AFR) AF: 0.218 AC: 9062 AN: 41478

American (AMR) AF: 0.176 AC: 2697 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 696 AN: 3468

East Asian (EAS) AF: 0.0663 AC: 344 AN: 5186

South Asian (SAS) AF: 0.173 AC: 833 AN: 4820

European-Finnish (FIN) AF: 0.162 AC: 1713 AN: 10584

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16186 AN: 67984

Other (OTH) AF: 0.218 AC: 458 AN: 2102

Alfa AF: 0.225 Hom.: 17000

Bravo AF: 0.212

Asia WGS AF: 0.128 AC: 445 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Autism spectrum disorder Uncertain:1

Jul 28, 2023

Gene Friend Way, National Innovation Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

rs2814707 associated with ALS risk. ALS is a neurodegenerative disorder that can lead to fatal paralysis (PMID 20801717). In our study, 23 out of 250 children diagnosed with autism spectrum disorder are also heterozygotes for rs2814707. However, the frequency of this T allele is also very high in the Vietnamese population (around 10% in our studies). Therefore, this variant is classified as VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.5
DANN	Benign	0.81
PhyloP100		-0.52

Splicing

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

Other links and lift over

dbSNP: rs2814707; hg19: chr9-27536397;