9-27546767-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_018325.5(C9orf72):c.*1469T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 152,302 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0047 ( 3 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

C9orf72
NM_018325.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.41

Publications

1 publications found

Variant links:

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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
progressive myoclonus epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

C9orf72 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 9-27546767-A-T is Benign according to our data. Variant chr9-27546767-A-T is described in ClinVar as [Benign]. Clinvar id is 366484.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 711 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5 link	c.*1469T>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000380003.8	NP_060795.1	Q96LT7-1
C9orf72	NM_001256054.3 link	c.*1469T>A		3_prime_UTR_variant	Exon 11 of 11		NP_001242983.1	Q96LT7-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
C9orf72	ENST00000380003.8 link	c.*1469T>A	3_prime_UTR_variant	Exon 11 of 11	1	NM_018325.5	ENSP00000369339.3	Q96LT7-1
C9orf72	ENST00000619707.5 link	c.*1469T>A	3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000482753.1	Q96LT7-1
C9orf72	ENST00000488117.5 link	n.4596T>A	non_coding_transcript_exon_variant	Exon 10 of 10	2
C9orf72	ENST00000673600.1 link	n.*267+1348T>A	intron_variant	Intron 11 of 11			ENSP00000500650.1	A0A5F9ZHW7

Frequencies

GnomAD3 genomes

AF:

0.00468

AC:

712

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00797

Gnomad OTH

AF:

0.00239

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.00467

AC:

711

AN:

152302

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

337

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41570

American (AMR)

AF:

0.00144

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5194

South Asian (SAS)

AF:

0.00705

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00797

AC:

542

AN:

68006

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00283

Hom.:

Bravo

AF:

0.00415

Asia WGS

AF:

0.00260

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.4

(source)

DANN

Benign

0.77

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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9-27546767-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over