chr9-27548435-GAAA-G

Variant names:

• chr9-27548435-GAAA-G
• rs11292923
• NM_018325.5:c.1260-16_1260-14delTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018325.5(C9orf72):​c.1260-16_1260-14delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 173,110 control chromosomes in the GnomAD database, including 4,455 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (1990 hom., cov: 0)
  • Exomes 𝑓: 0.31 (2465 hom.)
• Consequence: C9orf72 NM_018325.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0700
• 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 -10 ACMG points.

• BP6: Variant 9-27548435-GAAA-G is Benign according to our data. Variant chr9-27548435-GAAA-G is described in ClinVar as Benign. ClinVar VariationId is 366521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

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.1260-16_1260-14delTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-16_1260-14delTTT		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.1260-16_1260-14delTTT		intron	N/A	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.1260-16_1260-14delTTT		intron	N/A	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000644136.1		c.1293-16_1293-14delTTT		intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes AF: 0.424 AC: 15633 AN: 36902 Hom.: 1997 Cov.: 0

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.439

GnomAD4 exome AF: 0.310 AC: 42257 AN: 136216 Hom.: 2465 AF XY: 0.304 AC XY: 21371 AN XY: 70376

African (AFR) AF: 0.162 AC: 490 AN: 3034

American (AMR) AF: 0.225 AC: 1253 AN: 5578

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1174 AN: 3660

East Asian (EAS) AF: 0.319 AC: 4226 AN: 13244

South Asian (SAS) AF: 0.190 AC: 1488 AN: 7846

European-Finnish (FIN) AF: 0.288 AC: 2290 AN: 7948

Middle Eastern (MID) AF: 0.258 AC: 135 AN: 524

European-Non Finnish (NFE) AF: 0.333 AC: 29171 AN: 87574

Other (OTH) AF: 0.298 AC: 2030 AN: 6808

GnomAD4 genome AF: 0.423 AC: 15617 AN: 36894 Hom.: 1990 Cov.: 0 AF XY: 0.425 AC XY: 6885 AN XY: 16208

African (AFR) AF: 0.260 AC: 2131 AN: 8184

American (AMR) AF: 0.463 AC: 1446 AN: 3126

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 675 AN: 1362

East Asian (EAS) AF: 0.448 AC: 656 AN: 1464

South Asian (SAS) AF: 0.403 AC: 289 AN: 718

European-Finnish (FIN) AF: 0.636 AC: 248 AN: 390

Middle Eastern (MID) AF: 0.540 AC: 27 AN: 50

European-Non Finnish (NFE) AF: 0.471 AC: 9773 AN: 20764

Other (OTH) AF: 0.439 AC: 215 AN: 490

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

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		-0.070
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11292923; hg19: chr9-27548433;