9-27557921-T-C

Variant names:

• chr9-27557921-T-C
• rs10757665
• NM_018325.5:c.855+570A>G

Variant summary

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

The ENST00000380003.8(C9orf72):​c.855+570A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 151,720 control chromosomes in the GnomAD database, including 3,098 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 0.19 (3098 hom., cov: 32)
• Consequence: C9orf72 ENST00000380003.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.186
• Publications: 8 publications found

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]

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380003.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	NM_018325.5	MANE Select	c.855+570A>G		intron	N/A	NP_060795.1
	C9orf72	NM_001256054.3		c.855+570A>G		intron	N/A	NP_001242983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.855+570A>G		intron	N/A	ENSP00000369339.3
	C9orf72	ENST00000619707.5	TSL:1	c.855+570A>G		intron	N/A	ENSP00000482753.1
	C9orf72	ENST00000644136.1		c.855+570A>G		intron	N/A	ENSP00000494872.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29508 AN: 151606 Hom.: 3097 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.195 AC: 29511 AN: 151720 Hom.: 3098 Cov.: 32 AF XY: 0.193 AC XY: 14279 AN XY: 74160

African (AFR) AF: 0.141 AC: 5855 AN: 41470

American (AMR) AF: 0.152 AC: 2321 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 869 AN: 3464

East Asian (EAS) AF: 0.112 AC: 584 AN: 5194

South Asian (SAS) AF: 0.197 AC: 948 AN: 4824

European-Finnish (FIN) AF: 0.238 AC: 2476 AN: 10410

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.234 AC: 15901 AN: 67814

Other (OTH) AF: 0.185 AC: 389 AN: 2104

Alfa AF: 0.220 Hom.: 1960

Bravo AF: 0.182

Asia WGS AF: 0.177 AC: 609 AN: 3456

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.3
DANN	Benign	0.66
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10757665; hg19: chr9-27557919; COSMIC: COSV66155048; COSMIC: COSV66155048;