rs774359

chr9-27561051-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018325.5(C9orf72):c.665+534A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 179,578 control chromosomes in the GnomAD database, including 5,012 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 0.23 (4044 hom., cov: 32)
  • Exomes 𝑓: 0.26 (968 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_018325.5	c.665+534A>G		intron_variant		ENST00000380003.8
C9orf72	NM_145005.7	c.*530A>G		3_prime_UTR_variant	5/5
C9orf72	NM_001256054.3	c.665+534A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8	c.665+534A>G		intron_variant		1	NM_018325.5	P1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34286 AN: 151818 Hom.: 4036 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.0953

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.235

GnomAD4 exome AF: 0.264 AC: 7298 AN: 27642 Hom.: 968 Cov.: 4 AF XY: 0.262 AC XY: 3552 AN XY: 13564

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.0789

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.226 AC: 34320 AN: 151936 Hom.: 4044 Cov.: 32 AF XY: 0.222 AC XY: 16451 AN XY: 74260

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.0954

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.233

Alfa AF: 0.249 Hom.: 8447

Bravo AF: 0.224

Asia WGS AF: 0.167 AC: 581 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.0
Dann	Benign	0.54

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: rs774359; hg19: chr9-27561049;