9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAAAA

Variant names:

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

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-19_1260-14dupTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 18 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.1260-19_1260-14dupTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-19_1260-14dupTTTTTT		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_1260-14dupTTTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-19_1260-14dupTTTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-19_1293-14dupTTTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.000489 AC: 18 AN: 36774 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000613

Gnomad AMI AF: 0.00287

Gnomad AMR AF: 0.000323

Gnomad ASJ AF: 0.000735

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000386

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00129 AC: 178 AN: 138056 Hom.: 1 Cov.: 0 AF XY: 0.00150 AC XY: 107 AN XY: 71336

⚠️ 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: 3098

American (AMR) AF: 0.000530 AC: 3 AN: 5658

Ashkenazi Jewish (ASJ) AF: 0.00242 AC: 9 AN: 3722

East Asian (EAS) AF: 0.00149 AC: 20 AN: 13452

South Asian (SAS) AF: 0.000755 AC: 6 AN: 7942

European-Finnish (FIN) AF: 0.00186 AC: 15 AN: 8058

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

European-Non Finnish (NFE) AF: 0.00133 AC: 118 AN: 88662

Other (OTH) AF: 0.000866 AC: 6 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: 0.000490 AC: 18 AN: 36766 Hom.: 1 Cov.: 0 AF XY: 0.000620 AC XY: 10 AN XY: 16136

African (AFR) AF: 0.000612 AC: 5 AN: 8168

American (AMR) AF: 0.000323 AC: 1 AN: 3100

Ashkenazi Jewish (ASJ) AF: 0.000735 AC: 1 AN: 1360

East Asian (EAS) AF: 0.00138 AC: 2 AN: 1454

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: 0.000387 AC: 8 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		-0.24

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;