Genetic Variant C9orf72:c.1260-14delT (chr9-27548435-GA-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_018325.5(C9orf72):c.1260-14delT 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 0.058 ( 38 hom., cov: 0)

Exomes 𝑓: 0.030 ( 12 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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 Benign. Variant got -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5 link	c.1260-14delT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1	Q96LT7-1
C9orf72	NM_001256054.3 link	c.1260-14delT		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.1260-14delT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3		Q96LT7-1

Frequencies

GnomAD3 genomes

AF:

0.0580

AC:

2129

AN:

36708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0779

Gnomad AMI

AF:

0.0345

Gnomad AMR

AF:

0.0399

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.0761

Gnomad SAS

AF:

0.0674

Gnomad FIN

AF:

0.0129

Gnomad MID

AF:

0.0172

Gnomad NFE

AF:

0.0546

Gnomad OTH

AF:

0.0531

GnomAD4 exome

AF:

0.0296

AC:

4045

AN:

136734

Hom.:

Cov.:

AF XY:

0.0289

AC XY:

2041

AN XY:

70668

show subpopulations

Gnomad4 AFR exome

AF:

0.0680

Gnomad4 AMR exome

AF:

0.0187

Gnomad4 ASJ exome

AF:

0.0239

Gnomad4 EAS exome

AF:

0.0414

Gnomad4 SAS exome

AF:

0.0228

Gnomad4 FIN exome

AF:

0.0232

Gnomad4 NFE exome

AF:

0.0284

Gnomad4 OTH exome

AF:

0.0303

GnomAD4 genome

AF:

0.0580

AC:

2130

AN:

36700

Hom.:

Cov.:

AF XY:

0.0578

AC XY:

931

AN XY:

16114

show subpopulations

Gnomad4 AFR

AF:

0.0779

Gnomad4 AMR

AF:

0.0398

Gnomad4 ASJ

AF:

0.0303

Gnomad4 EAS

AF:

0.0764

Gnomad4 SAS

AF:

0.0690

Gnomad4 FIN

AF:

0.0129

Gnomad4 NFE

AF:

0.0545

Gnomad4 OTH

AF:

0.0531

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Uncertain:1

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-GAAAAAAAAAAAAAAAAA

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