NM_018325.5:c.*1406T>C

Variant names:

• chr9-27546830-A-G
• rs9103
• NM_018325.5:c.*1406T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018325.5(C9orf72):​c.*1406T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,108 control chromosomes in the GnomAD database, including 3,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3549 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: C9orf72 NM_018325.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.216
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-27546830-A-G is Benign according to our data. Variant chr9-27546830-A-G is described in ClinVar as Benign. ClinVar VariationId is 366485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.248 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.*1406T>C		3_prime_UTR	Exon 11 of 11	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.*1406T>C		3_prime_UTR	Exon 11 of 11	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.*1406T>C		3_prime_UTR	Exon 11 of 11	ENSP00000369339.3	Q96LT7-1
	C9orf72	ENST00000619707.5	TSL:1	c.*1406T>C		3_prime_UTR	Exon 11 of 11	ENSP00000482753.1	Q96LT7-1
	C9orf72	ENST00000965249.1		c.*1406T>C		3_prime_UTR	Exon 12 of 12	ENSP00000635308.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31469 AN: 151990 Hom.: 3548 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.191

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.207 AC: 31474 AN: 152108 Hom.: 3549 Cov.: 32 AF XY: 0.206 AC XY: 15337 AN XY: 74348

African (AFR) AF: 0.144 AC: 5975 AN: 41520

American (AMR) AF: 0.156 AC: 2383 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 831 AN: 3464

East Asian (EAS) AF: 0.119 AC: 615 AN: 5180

South Asian (SAS) AF: 0.203 AC: 981 AN: 4822

European-Finnish (FIN) AF: 0.287 AC: 3031 AN: 10562

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17078 AN: 67952

Other (OTH) AF: 0.194 AC: 409 AN: 2110

Alfa AF: 0.218 Hom.: 1531

Bravo AF: 0.190

Asia WGS AF: 0.182 AC: 631 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.75
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs9103; hg19: chr9-27546828; COSMIC: COSV66163921; COSMIC: COSV66163921;