rs10967976

chr9-27544945-G-Achr9-27544945-G-Cchr9-27544945-G-T

Variant summary

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

The ENST00000673600.1(C9orf72):c.*267+3170C>T variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 152,014 control chromosomes in the GnomAD database, including 16,527 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 0.43 (16527 hom., cov: 32)
• Consequence: C9orf72 ENST00000673600.1 intron, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.411

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=-0.5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000673600.1	c.*267+3170C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65158 AN: 151896 Hom.: 16533 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.429 AC: 65143 AN: 152014 Hom.: 16527 Cov.: 32 AF XY: 0.434 AC XY: 32278 AN XY: 74288

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.640

Gnomad4 EAS AF: 0.599

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.534

Gnomad4 OTH AF: 0.444

Alfa AF: 0.501 Hom.: 8822

Bravo AF: 0.408

Asia WGS AF: 0.475 AC: 1650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	2.2
Dann	Benign	0.93

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10967976; hg19: chr9-27544943; COSMIC: COSV66163351;