rs10967977

Variant names:

• chr9-27545080-A-G
• rs10967977
• ENST00000673600.1:n.*267+3035T>C

Variant summary

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

The ENST00000673600.1(C9orf72):​n.*267+3035T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,240 control chromosomes in the GnomAD database, including 1,968 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 0.14 (1968 hom., cov: 32)
• Consequence: C9orf72 ENST00000673600.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 1 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000673600.1	n.*267+3035T>C		intron_variant	Intron 11 of 11			ENSP00000500650.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21639 AN: 152122 Hom.: 1972 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.152

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

GnomAD4 genome AF: 0.142 AC: 21631 AN: 152240 Hom.: 1968 Cov.: 32 AF XY: 0.142 AC XY: 10593 AN XY: 74422

African (AFR) AF: 0.0328 AC: 1363 AN: 41584

American (AMR) AF: 0.112 AC: 1716 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 918 AN: 3466

East Asian (EAS) AF: 0.160 AC: 830 AN: 5184

South Asian (SAS) AF: 0.129 AC: 620 AN: 4824

European-Finnish (FIN) AF: 0.221 AC: 2339 AN: 10580

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13303 AN: 67978

Other (OTH) AF: 0.150 AC: 317 AN: 2116

Alfa AF: 0.162 Hom.: 301

Bravo AF: 0.130

Asia WGS AF: 0.107 AC: 373 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.1
DANN	Benign	0.76
PhyloP100		1.1

Splicing

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

Other links and lift over

dbSNP: rs10967977; hg19: chr9-27545078;