9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-G-GAAA
• rs11292923
• NM_018325.5:c.1260-16_1260-14dupTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-16_1260-14dupTTT 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 0.00041 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0040 (4 hom.)
• 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 GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5	c.1260-16_1260-14dupTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1
C9orf72	NM_001256054.3	c.1260-16_1260-14dupTTT		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_1260-13insTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 15 AN: 36772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000686

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000580

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00401 AC: 553 AN: 137856 Hom.: 4 Cov.: 0 AF XY: 0.00415 AC XY: 296 AN XY: 71246

Gnomad4 AFR exome AF: 0.00259

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00484

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.00353

Gnomad4 FIN exome AF: 0.00597

Gnomad4 NFE exome AF: 0.00441

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.000408 AC: 15 AN: 36764 Hom.: 0 Cov.: 0 AF XY: 0.000496 AC XY: 8 AN XY: 16134

Gnomad4 AFR AF: 0.000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000689

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000580

Gnomad4 OTH AF: 0.00

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

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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;