rs13691

chr9-27546892-G-Achr9-27546892-G-Cchr9-27546892-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018325.5(C9orf72):c.*1344C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,000 control chromosomes in the GnomAD database, including 4,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4677 hom., cov: 32)
  • Exomes 𝑓: 0.33 (0 hom.)
• Consequence: C9orf72 NM_018325.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.696

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-27546892-G-A is Benign according to our data. Variant chr9-27546892-G-A is described in ClinVar as [Benign]. Clinvar id is 366486.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_018325.5	c.*1344C>T		3_prime_UTR_variant	11/11	ENST00000380003.8
C9orf72	NM_001256054.3	c.*1344C>T		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8	c.*1344C>T		3_prime_UTR_variant	11/11	1	NM_018325.5	P1
C9orf72	ENST00000619707.5	c.*1344C>T		3_prime_UTR_variant	11/11	1		P1
C9orf72	ENST00000488117.5	n.4471C>T		non_coding_transcript_exon_variant	10/10	2
C9orf72	ENST00000673600.1	c.*267+1223C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34010 AN: 151878 Hom.: 4674 Cov.: 32

Gnomad AFR AF: 0.0845

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.333 AC: 2 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.333

GnomAD4 genome AF: 0.224 AC: 34009 AN: 151994 Hom.: 4677 Cov.: 32 AF XY: 0.230 AC XY: 17080 AN XY: 74276

Gnomad4 AFR AF: 0.0843

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.391

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.229

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.256

Alfa AF: 0.255 Hom.: 9195

Bravo AF: 0.227

Asia WGS AF: 0.333 AC: 1159 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.43
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs13691; hg19: chr9-27546890; COSMIC: COSV66163359; COSMIC: COSV66163359;