rs10967977

Positions:

• chr9-27545080-A-G

Variant summary

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

The ENST00000673600.1(C9orf72):​c.*267+3035T>C variant causes a intron, NMD transcript 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, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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 = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000673600.1	c.*267+3035T>C		intron_variant, NMD_transcript_variant				ENSP00000500650

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

Gnomad4 AFR AF: 0.0328

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.150

Alfa AF: 0.167 Hom.: 298

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10967977; hg19: chr9-27545078;