9-27536399-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMICERI	ENST00000645861.1	n.1097C>T		non_coding_transcript_exon_variant	2/2
C9orf72	ENST00000673600.1	c.*268-113G>A		intron_variant, NMD_transcript_variant

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

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.0663

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.218

Alfa AF: 0.226 Hom.: 8900

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

Uncertain significance, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2814707; hg19: chr9-27536397;