rs143561967

chr9-27573523-CGCCCCGGCCCCG-Cchr9-27573523-CGCCCCGGCCCCG-CGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCAGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGTCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCCGGGCCCCGGCCCCGchr9-27573523-CGCCCCGGCCCCG-CGCCCCGGCCCCGGCCCCGGCCCCGGCCGCGGCCCCGGCCCCG

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000619707.5(C9orf72):c.-45+174_-45+185del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000423 in 141,698 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 ENST00000619707.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9orf72	NM_001256054.3	c.-45+174_-45+185del		intron_variant
C9orf72	NM_145005.7	c.-45+252_-45+263del		intron_variant
C9orf72	NM_018325.5			upstream_gene_variant		ENST00000380003.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9orf72	ENST00000380003.8			upstream_gene_variant		1	NM_018325.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000423 AC: 6 AN: 141698 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 700 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 328

Gnomad4 SAS exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000423 AC: 6 AN: 141698 Hom.: 0 Cov.: 0 AF XY: 0.0000291 AC XY: 2 AN XY: 68822

Gnomad4 AFR AF: 0.000154

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143561967; hg19: chr9-27573521;