9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAA

Variant names:

• chr9-27548435-GAAAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-21_1260-14delTTTTTTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-21_1260-14delTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.000721 in 174,776 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 0.00038 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00081 (0 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15

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 GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-21_1260-14delTTTTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-21_1260-14delTTTTTTTT		intron_variant	Intron 10 of 10		NP_001242983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8	c.1260-21_1260-14delTTTTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.000354 AC: 13 AN: 36772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00226

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: 0.000145

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000812 AC: 112 AN: 138012 Hom.: 0 AF XY: 0.000715 AC XY: 51 AN XY: 71324

Gnomad4 AFR exome AF: 0.000323

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.000537

Gnomad4 EAS exome AF: 0.00126

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000496

Gnomad4 NFE exome AF: 0.000700

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000381 AC: 14 AN: 36764 Hom.: 0 Cov.: 0 AF XY: 0.000372 AC XY: 6 AN XY: 16134

Gnomad4 AFR AF: 0.000490

Gnomad4 AMR AF: 0.00226

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000145

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: rs11292923; hg19: chr9-27548433;