9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAA

Variant names:

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

Variant summary

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

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

• Frequency:
  • Genomes: 𝑓 0.11 (449 hom., cov: 0)
  • Exomes 𝑓: 0.017 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• 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: 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.1260-14dupT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-14dupT		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.1260-14_1260-13insT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-14_1260-13insT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-14_1293-13insT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.114 AC: 4183 AN: 36670 Hom.: 449 Cov.: 0

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.0644

Gnomad FIN AF: 0.0492

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.0166 AC: 2288 AN: 137630 Hom.: 5 Cov.: 0 AF XY: 0.0172 AC XY: 1225 AN XY: 71108

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

African (AFR) AF: 0.0331 AC: 102 AN: 3080

American (AMR) AF: 0.0112 AC: 63 AN: 5638

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 56 AN: 3712

East Asian (EAS) AF: 0.00722 AC: 97 AN: 13430

South Asian (SAS) AF: 0.00984 AC: 78 AN: 7930

European-Finnish (FIN) AF: 0.0170 AC: 137 AN: 8040

Middle Eastern (MID) AF: 0.0336 AC: 18 AN: 536

European-Non Finnish (NFE) AF: 0.0181 AC: 1603 AN: 88368

Other (OTH) AF: 0.0194 AC: 134 AN: 6896

⚠️ 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: 0.114 AC: 4186 AN: 36662 Hom.: 449 Cov.: 0 AF XY: 0.113 AC XY: 1815 AN XY: 16094

African (AFR) AF: 0.127 AC: 1035 AN: 8152

American (AMR) AF: 0.0902 AC: 278 AN: 3082

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 144 AN: 1358

East Asian (EAS) AF: 0.0359 AC: 52 AN: 1450

South Asian (SAS) AF: 0.0646 AC: 46 AN: 712

European-Finnish (FIN) AF: 0.0492 AC: 19 AN: 386

Middle Eastern (MID) AF: 0.120 AC: 6 AN: 50

European-Non Finnish (NFE) AF: 0.121 AC: 2501 AN: 20638

Other (OTH) AF: 0.123 AC: 60 AN: 486

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	3	-	Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (3)

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;