rs1565948

chr9-27559735-G-A

Variant summary

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

The NM_018325.5(C9orf72):c.738+492C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 151,906 control chromosomes in the GnomAD database, including 15,096 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 0.44 (15093 hom., cov: 32)
  • Exomes 𝑓: 0.56 (3 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.235

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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_018325.5	c.738+492C>T		intron_variant		ENST00000380003.8
C9orf72	NM_001256054.3	c.738+492C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8	c.738+492C>T		intron_variant		1	NM_018325.5	P1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66175 AN: 151770 Hom.: 15080 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.418

GnomAD4 exome AF: 0.556 AC: 10 AN: 18 Hom.: 3 Cov.: 0 AF XY: 0.875 AC XY: 7 AN XY: 8

Gnomad4 NFE exome AF: 0.556

GnomAD4 genome AF: 0.436 AC: 66216 AN: 151888 Hom.: 15093 Cov.: 32 AF XY: 0.437 AC XY: 32428 AN XY: 74244

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.555

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.424

Alfa AF: 0.483 Hom.: 25883

Bravo AF: 0.420

Asia WGS AF: 0.489 AC: 1690 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.8
Dann	Benign	0.65

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: rs1565948; hg19: chr9-27559733;