9-27548435-GAAAAAAAAAA-G

Variant names:

• chr9-27548435-GAAAAAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-23_1260-14delTTTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_018325.5(C9orf72):​c.1260-23_1260-14delTTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.00215 in 174,878 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (3 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00176 (243/138114) while in subpopulation AFR AF = 0.03 (93/3098). AF 95% confidence interval is 0.0251. There are 3 homozygotes in GnomAdExome4. There are 115 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High AC in GnomAd4 at 133 AD gene.

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.1260-23_1260-14delTTTTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-23_1260-14delTTTTTTTTTT		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.1260-23_1260-14delTTTTTTTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-23_1260-14delTTTTTTTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-23_1293-14delTTTTTTTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 133 AN: 36772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000646

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00279

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000580

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00176 AC: 243 AN: 138114 Hom.: 3 AF XY: 0.00161 AC XY: 115 AN XY: 71370

African (AFR) AF: 0.0300 AC: 93 AN: 3098

American (AMR) AF: 0.000177 AC: 1 AN: 5658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3728

East Asian (EAS) AF: 0.0000743 AC: 1 AN: 13460

South Asian (SAS) AF: 0.00189 AC: 15 AN: 7942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8070

Middle Eastern (MID) AF: 0.00372 AC: 2 AN: 538

European-Non Finnish (NFE) AF: 0.00133 AC: 118 AN: 88686

Other (OTH) AF: 0.00187 AC: 13 AN: 6934

GnomAD4 genome AF: 0.00362 AC: 133 AN: 36764 Hom.: 0 Cov.: 0 AF XY: 0.00459 AC XY: 74 AN XY: 16132

African (AFR) AF: 0.0143 AC: 117 AN: 8168

American (AMR) AF: 0.000645 AC: 2 AN: 3100

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1452

South Asian (SAS) AF: 0.00280 AC: 2 AN: 714

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

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

European-Non Finnish (NFE) AF: 0.000580 AC: 12 AN: 20694

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;