9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018325.5(C9orf72):​c.1260-17_1260-14delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 136,160 control chromosomes in the GnomAD database, including 207 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.039 (76 hom., cov: 0)
  • Exomes 𝑓: 0.17 (207 hom.)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.477
• Publications: 1 publications found

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]

C9orf72 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• progressive myoclonus epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	NM_018325.5	MANE Select	c.1260-17_1260-14delTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-17_1260-14delTTTT		intron	N/A	NP_001242983.1	Q96LT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.1260-17_1260-14delTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-17_1260-14delTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-17_1293-14delTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 1435 AN: 36812 Hom.: 74 Cov.: 0

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0460

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0169

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.0531

GnomAD4 exome AF: 0.170 AC: 23102 AN: 136160 Hom.: 207 AF XY: 0.168 AC XY: 11848 AN XY: 70324

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0765 AC: 234 AN: 3058

American (AMR) AF: 0.221 AC: 1227 AN: 5560

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 672 AN: 3664

East Asian (EAS) AF: 0.247 AC: 3257 AN: 13210

South Asian (SAS) AF: 0.157 AC: 1224 AN: 7818

European-Finnish (FIN) AF: 0.188 AC: 1492 AN: 7938

Middle Eastern (MID) AF: 0.133 AC: 70 AN: 528

European-Non Finnish (NFE) AF: 0.157 AC: 13716 AN: 87550

Other (OTH) AF: 0.177 AC: 1210 AN: 6834

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0391 AC: 1438 AN: 36804 Hom.: 76 Cov.: 0 AF XY: 0.0442 AC XY: 715 AN XY: 16160

African (AFR) AF: 0.0106 AC: 87 AN: 8170

American (AMR) AF: 0.145 AC: 450 AN: 3112

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 23 AN: 1360

East Asian (EAS) AF: 0.222 AC: 327 AN: 1472

South Asian (SAS) AF: 0.140 AC: 100 AN: 712

European-Finnish (FIN) AF: 0.0974 AC: 38 AN: 390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.0179 AC: 371 AN: 20700

Other (OTH) AF: 0.0531 AC: 26 AN: 490

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11292923; hg19: chr9-27548433;