9-27567147-C-T

Position:

• chr9-27567147-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018325.5(C9orf72):​c.-27G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,583,956 control chromosomes in the GnomAD database, including 39,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3228 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36070 hom.)
• Consequence: C9orf72 NM_018325.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.293

Genes affected

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-27567147-C-T is Benign according to our data. Variant chr9-27567147-C-T is described in ClinVar as [Benign]. Clinvar id is 366529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_018325.5	c.-27G>A		5_prime_UTR_variant	2/11	ENST00000380003.8
C9orf72	NM_001256054.3	c.-27G>A		5_prime_UTR_variant	2/11
C9orf72	NM_145005.7	c.-27G>A		5_prime_UTR_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8	c.-27G>A		5_prime_UTR_variant	2/11	1	NM_018325.5	P1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30424 AN: 151944 Hom.: 3223 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.199 AC: 48545 AN: 244534 Hom.: 5183 AF XY: 0.203 AC XY: 26923 AN XY: 132744

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.205

GnomAD4 exome AF: 0.221 AC: 316404 AN: 1431894 Hom.: 36070 Cov.: 26 AF XY: 0.221 AC XY: 157195 AN XY: 712710

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.200 AC: 30436 AN: 152062 Hom.: 3228 Cov.: 32 AF XY: 0.198 AC XY: 14733 AN XY: 74330

Gnomad4 AFR AF: 0.163

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.188

Alfa AF: 0.219 Hom.: 4547

Bravo AF: 0.188

Asia WGS AF: 0.178 AC: 617 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.3
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 17

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

Publications

LitVar

Other links and lift over

dbSNP: rs10757668; hg19: chr9-27567145; COSMIC: COSV66154683;