9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-GAA-G
• rs11292923
• NM_018325.5:c.1260-15_1260-14delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_018325.5(C9orf72):​c.1260-15_1260-14delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0708 in 172,814 control chromosomes in the GnomAD database, including 156 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.033 (20 hom., cov: 0)
  • Exomes 𝑓: 0.081 (136 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

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.1260-15_1260-14delTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-15_1260-14delTT		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.1260-15_1260-14delTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-15_1260-14delTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-15_1293-14delTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 1215 AN: 36770 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00287

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00549

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0333

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0469

GnomAD4 exome AF: 0.0810 AC: 11020 AN: 136052 Hom.: 136 AF XY: 0.0799 AC XY: 5620 AN XY: 70354

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

African (AFR) AF: 0.103 AC: 313 AN: 3046

American (AMR) AF: 0.0599 AC: 334 AN: 5576

Ashkenazi Jewish (ASJ) AF: 0.0839 AC: 308 AN: 3670

East Asian (EAS) AF: 0.0895 AC: 1173 AN: 13108

South Asian (SAS) AF: 0.0587 AC: 461 AN: 7860

European-Finnish (FIN) AF: 0.0732 AC: 581 AN: 7942

Middle Eastern (MID) AF: 0.0730 AC: 39 AN: 534

European-Non Finnish (NFE) AF: 0.0825 AC: 7220 AN: 87500

Other (OTH) AF: 0.0867 AC: 591 AN: 6816

⚠️ 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 AF: 0.0330 AC: 1214 AN: 36762 Hom.: 20 Cov.: 0 AF XY: 0.0343 AC XY: 553 AN XY: 16136

African (AFR) AF: 0.101 AC: 828 AN: 8164

American (AMR) AF: 0.0194 AC: 60 AN: 3100

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 35 AN: 1360

East Asian (EAS) AF: 0.00551 AC: 8 AN: 1452

South Asian (SAS) AF: 0.0182 AC: 13 AN: 714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 388

Middle Eastern (MID) AF: 0.0192 AC: 1 AN: 52

European-Non Finnish (NFE) AF: 0.0118 AC: 245 AN: 20694

Other (OTH) AF: 0.0469 AC: 23 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		-0.24
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;