9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAA

Variant names:

• chr9-27548435-GAAAAAAAA-G
• rs11292923
• NM_018325.5:c.1260-21_1260-14delTTTTTTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-21_1260-14delTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.000721 in 174,776 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 0.00038 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00081 (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 14 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.1260-21_1260-14delTTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-21_1260-14delTTTTTTTT		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.1260-21_1260-14delTTTTTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-21_1260-14delTTTTTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-21_1293-14delTTTTTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.000354 AC: 13 AN: 36772 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000368

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00226

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: 0.000145

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000812 AC: 112 AN: 138012 Hom.: 0 AF XY: 0.000715 AC XY: 51 AN XY: 71324

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

African (AFR) AF: 0.000323 AC: 1 AN: 3100

American (AMR) AF: 0.00195 AC: 11 AN: 5646

Ashkenazi Jewish (ASJ) AF: 0.000537 AC: 2 AN: 3722

East Asian (EAS) AF: 0.00126 AC: 17 AN: 13446

South Asian (SAS) AF: 0.00101 AC: 8 AN: 7938

European-Finnish (FIN) AF: 0.000496 AC: 4 AN: 8058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 538

European-Non Finnish (NFE) AF: 0.000700 AC: 62 AN: 88632

Other (OTH) AF: 0.00101 AC: 7 AN: 6932

⚠️ 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: 0.000381 AC: 14 AN: 36764 Hom.: 0 Cov.: 0 AF XY: 0.000372 AC XY: 6 AN XY: 16134

African (AFR) AF: 0.000490 AC: 4 AN: 8168

American (AMR) AF: 0.00226 AC: 7 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: 0.00 AC: 0 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: 0.000145 AC: 3 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;