9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAA

Variant names:

• chr9-27548435-GAAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-20_1260-14delTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018325.5(C9orf72):​c.1260-20_1260-14delTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.00248 in 174,502 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0031 (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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 11 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.1260-20_1260-14delTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-20_1260-14delTTTTTTT		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.1260-20_1260-14delTTTTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-20_1260-14delTTTTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-20_1293-14delTTTTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.000299 AC: 11 AN: 36772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000245

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: 0.000435

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00306 AC: 422 AN: 137730 Hom.: 0 AF XY: 0.00319 AC XY: 227 AN XY: 71190

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

African (AFR) AF: 0.00129 AC: 4 AN: 3100

American (AMR) AF: 0.00656 AC: 37 AN: 5638

Ashkenazi Jewish (ASJ) AF: 0.00377 AC: 14 AN: 3714

East Asian (EAS) AF: 0.00478 AC: 64 AN: 13376

South Asian (SAS) AF: 0.00278 AC: 22 AN: 7926

European-Finnish (FIN) AF: 0.00249 AC: 20 AN: 8042

Middle Eastern (MID) AF: 0.00186 AC: 1 AN: 538

European-Non Finnish (NFE) AF: 0.00277 AC: 245 AN: 88470

Other (OTH) AF: 0.00217 AC: 15 AN: 6926

⚠️ 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: 0.000299 AC: 11 AN: 36772 Hom.: 0 Cov.: 0 AF XY: 0.000248 AC XY: 4 AN XY: 16126

African (AFR) AF: 0.000245 AC: 2 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: 0.000435 AC: 9 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;