9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr9-27548435-G-GAAAA
• rs11292923
• NM_018325.5:c.1260-17_1260-14dupTTTT

Variant summary

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

The NM_018325.5(C9orf72):​c.1260-17_1260-14dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.066 (116 hom., cov: 0)
  • Exomes 𝑓: 0.0094 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: 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.1260-17_1260-14dupTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-17_1260-14dupTTTT		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.1260-17_1260-14dupTTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-17_1260-14dupTTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-17_1293-14dupTTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 2417 AN: 36672 Hom.: 116 Cov.: 0

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0578

Gnomad AMR AF: 0.0496

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.0630

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0862

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0410

GnomAD4 exome AF: 0.00937 AC: 1288 AN: 137520 Hom.: 10 Cov.: 0 AF XY: 0.00959 AC XY: 681 AN XY: 71042

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

African (AFR) AF: 0.00550 AC: 17 AN: 3090

American (AMR) AF: 0.00337 AC: 19 AN: 5644

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 48 AN: 3702

East Asian (EAS) AF: 0.00537 AC: 72 AN: 13406

South Asian (SAS) AF: 0.00428 AC: 34 AN: 7938

European-Finnish (FIN) AF: 0.0158 AC: 126 AN: 7998

Middle Eastern (MID) AF: 0.00746 AC: 4 AN: 536

European-Non Finnish (NFE) AF: 0.0103 AC: 905 AN: 88284

Other (OTH) AF: 0.00910 AC: 63 AN: 6922

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0658 AC: 2414 AN: 36664 Hom.: 116 Cov.: 0 AF XY: 0.0604 AC XY: 971 AN XY: 16074

African (AFR) AF: 0.0363 AC: 296 AN: 8150

American (AMR) AF: 0.0498 AC: 154 AN: 3090

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 142 AN: 1360

East Asian (EAS) AF: 0.0352 AC: 51 AN: 1448

South Asian (SAS) AF: 0.0632 AC: 45 AN: 712

European-Finnish (FIN) AF: 0.0648 AC: 25 AN: 386

Middle Eastern (MID) AF: 0.0800 AC: 4 AN: 50

European-Non Finnish (NFE) AF: 0.0803 AC: 1657 AN: 20634

Other (OTH) AF: 0.0410 AC: 20 AN: 488

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.24
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;