9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-G-GAAAA
• rs11292923
• NM_018325.5:c.1260-17_1260-14dupTTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-17_1260-14dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.066 (116 hom., cov: 0)
  • Exomes 𝑓: 0.0094 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.242

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 GnomAdExome4 at 1288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-17_1260-14dupTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-17_1260-14dupTTTT		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.1260-14_1260-13insTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2417 AN: 36672 Hom.: 116 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0578

Gnomad AMR AF: 0.0496

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.0630

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0862

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0410

GnomAD4 exome AF: 0.00937 AC: 1288 AN: 137520 Hom.: 10 Cov.: 0 AF XY: 0.00959 AC XY: 681 AN XY: 71042

Gnomad4 AFR exome AF: 0.00550

Gnomad4 AMR exome AF: 0.00337

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.00537

Gnomad4 SAS exome AF: 0.00428

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00910

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0658 AC: 2414 AN: 36664 Hom.: 116 Cov.: 0 AF XY: 0.0604 AC XY: 971 AN XY: 16074

Gnomad4 AFR AF: 0.0363

Gnomad4 AMR AF: 0.0498

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.0352

Gnomad4 SAS AF: 0.0632

Gnomad4 FIN AF: 0.0648

Gnomad4 NFE AF: 0.0803

Gnomad4 OTH AF: 0.0410

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;