Genetic Variant NM_018325.5:c.1260-22_1260-14dupTTTTTTTTT (chr9-27548435-G-GAAAAAAAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_018325.5(C9orf72):c.1260-22_1260-14dupTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0081 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0032 ( 13 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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 -4 ACMG points.

BS2

High AC in GnomAd4 at 298 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5 link	c.1260-22_1260-14dupTTTTTTTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1	Q96LT7-1
C9orf72	NM_001256054.3 link	c.1260-22_1260-14dupTTTTTTTTT		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_1260-13insTTTTTTTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3		Q96LT7-1

Frequencies

GnomAD3 genomes

AF:

0.00810

AC:

298

AN:

36768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00417

Gnomad AMI

AF:

0.00862

Gnomad AMR

AF:

0.00259

Gnomad ASJ

AF:

0.0125

Gnomad EAS

AF:

0.00343

Gnomad SAS

AF:

0.00279

Gnomad FIN

AF:

0.00773

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00816

GnomAD4 exome

AF:

0.00319

AC:

440

AN:

138112

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

257

AN XY:

71368

show subpopulations

Gnomad4 AFR exome

AF:

0.00290

Gnomad4 AMR exome

AF:

0.00513

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.000520

Gnomad4 SAS exome

AF:

0.0117

Gnomad4 FIN exome

AF:

0.00223

Gnomad4 NFE exome

AF:

0.00294

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.00811

AC:

298

AN:

36760

Hom.:

Cov.:

AF XY:

0.00849

AC XY:

137

AN XY:

16136

show subpopulations

Gnomad4 AFR

AF:

0.00416

Gnomad4 AMR

AF:

0.00258

Gnomad4 ASJ

AF:

0.0125

Gnomad4 EAS

AF:

0.00344

Gnomad4 SAS

AF:

0.00280

Gnomad4 FIN

AF:

0.00773

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.00816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over