9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAA

Variant names:

• chr9-27548435-GAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-19_1260-14delTTTTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-19_1260-14delTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.00882 in 174,032 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000054 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (0 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.15
• 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.1260-19_1260-14delTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-19_1260-14delTTTTTT		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.1260-19_1260-14delTTTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-19_1260-14delTTTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-19_1293-14delTTTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.0000544 AC: 2 AN: 36772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000966

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0112 AC: 1533 AN: 137260 Hom.: 0 AF XY: 0.0113 AC XY: 805 AN XY: 70956

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

African (AFR) AF: 0.00226 AC: 7 AN: 3092

American (AMR) AF: 0.0221 AC: 124 AN: 5622

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 32 AN: 3702

East Asian (EAS) AF: 0.0203 AC: 271 AN: 13336

South Asian (SAS) AF: 0.0134 AC: 106 AN: 7896

European-Finnish (FIN) AF: 0.0141 AC: 113 AN: 7998

Middle Eastern (MID) AF: 0.00940 AC: 5 AN: 532

European-Non Finnish (NFE) AF: 0.00894 AC: 789 AN: 88216

Other (OTH) AF: 0.0125 AC: 86 AN: 6866

⚠️ 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: 0.0000544 AC: 2 AN: 36772 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16126

African (AFR) AF: 0.00 AC: 0 AN: 8160

American (AMR) AF: 0.00 AC: 0 AN: 3094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1360

East Asian (EAS) AF: 0.00 AC: 0 AN: 1458

South Asian (SAS) AF: 0.00 AC: 0 AN: 716

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 58

European-Non Finnish (NFE) AF: 0.0000966 AC: 2 AN: 20700

Other (OTH) AF: 0.00 AC: 0 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		5.1
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs11292923; hg19: chr9-27548433;