9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-GA-G
• rs11292923
• NM_018325.5:c.1260-14delT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-14delT 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 0.058 (38 hom., cov: 0)
  • Exomes 𝑓: 0.030 (12 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 = 0.0729 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.1260-14delT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-14delT		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.1260-14delT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-14delT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-14delT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 2129 AN: 36708 Hom.: 38 Cov.: 0

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.0345

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.0761

Gnomad SAS AF: 0.0674

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0531

GnomAD4 exome AF: 0.0296 AC: 4045 AN: 136734 Hom.: 12 Cov.: 0 AF XY: 0.0289 AC XY: 2041 AN XY: 70668

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

African (AFR) AF: 0.0680 AC: 209 AN: 3072

American (AMR) AF: 0.0187 AC: 105 AN: 5612

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 88 AN: 3688

East Asian (EAS) AF: 0.0414 AC: 547 AN: 13226

South Asian (SAS) AF: 0.0228 AC: 180 AN: 7878

European-Finnish (FIN) AF: 0.0232 AC: 186 AN: 8004

Middle Eastern (MID) AF: 0.0436 AC: 23 AN: 528

European-Non Finnish (NFE) AF: 0.0284 AC: 2499 AN: 87866

Other (OTH) AF: 0.0303 AC: 208 AN: 6860

⚠️ 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: 0.0580 AC: 2130 AN: 36700 Hom.: 38 Cov.: 0 AF XY: 0.0578 AC XY: 931 AN XY: 16114

African (AFR) AF: 0.0779 AC: 635 AN: 8148

American (AMR) AF: 0.0398 AC: 123 AN: 3088

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 41 AN: 1354

East Asian (EAS) AF: 0.0764 AC: 111 AN: 1452

South Asian (SAS) AF: 0.0690 AC: 49 AN: 710

European-Finnish (FIN) AF: 0.0129 AC: 5 AN: 388

Middle Eastern (MID) AF: 0.0200 AC: 1 AN: 50

European-Non Finnish (NFE) AF: 0.0545 AC: 1127 AN: 20672

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

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (1)
-	1	-	not provided (1)

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)		0.0		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;