Genetic Variant C9orf72:c.1260-14dupT (chr9-27548435-G-GA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

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

Frequency

Genomes: 𝑓 0.11 ( 449 hom., cov: 0)

Exomes 𝑓: 0.017 ( 5 hom. )

Failed GnomAD Quality Control

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: -0.242

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0166 (2288/137630) while in subpopulation MID AF= 0.0336 (18/536). AF 95% confidence interval is 0.0279. There are 5 homozygotes in gnomad4_exome. There are 1225 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 2288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5 link	c.1260-14dupT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1	Q96LT7-1
C9orf72	NM_001256054.3 link	c.1260-14dupT		intron_variant	Intron 10 of 10		NP_001242983.1	Q96LT7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C9orf72	ENST00000380003.8 link	c.1260-14_1260-13insT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3		Q96LT7-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

4183

AN:

36670

Hom.:

449

Cov.:

FAILED QC

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.0901

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0357

Gnomad SAS

AF:

0.0644

Gnomad FIN

AF:

0.0492

Gnomad MID

AF:

0.103

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.123

GnomAD4 exome

AF:

0.0166

AC:

2288

AN:

137630

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1225

AN XY:

71108

show subpopulations

Gnomad4 AFR exome

AF:

0.0331

Gnomad4 AMR exome

AF:

0.0112

Gnomad4 ASJ exome

AF:

0.0151

Gnomad4 EAS exome

AF:

0.00722

Gnomad4 SAS exome

AF:

0.00984

Gnomad4 FIN exome

AF:

0.0170

Gnomad4 NFE exome

AF:

0.0181

Gnomad4 OTH exome

AF:

0.0194

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.114

AC:

4186

AN:

36662

Hom.:

449

Cov.:

AF XY:

0.113

AC XY:

1815

AN XY:

16094

show subpopulations

Gnomad4 AFR

AF:

0.127

Gnomad4 AMR

AF:

0.0902

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.0359

Gnomad4 SAS

AF:

0.0646

Gnomad4 FIN

AF:

0.0492

Gnomad4 NFE

AF:

0.121

Gnomad4 OTH

AF:

0.123

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Uncertain:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over