Genetic Variant C9orf72:c.1260-16_1260-14delTTT (chr9-27548435-GAAA-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_018325.5(C9orf72):c.1260-16_1260-14delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 173,110 control chromosomes in the GnomAD database, including 4,455 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.42 ( 1990 hom., cov: 0)

Exomes 𝑓: 0.31 ( 2465 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0700

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 -10 ACMG points.

BP6

Variant 9-27548435-GAAA-G is Benign according to our data. Variant chr9-27548435-GAAA-G is described in ClinVar as [Benign]. Clinvar id is 366521.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C9orf72	NM_018325.5 link	c.1260-16_1260-14delTTT		intron_variant	Intron 10 of 10	ENST00000380003.8	NP_060795.1	Q96LT7-1
C9orf72	NM_001256054.3 link	c.1260-16_1260-14delTTT		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.1260-16_1260-14delTTT		intron_variant	Intron 10 of 10	1	NM_018325.5	ENSP00000369339.3		Q96LT7-1

Frequencies

GnomAD3 genomes

AF:

0.424

AC:

15633

AN:

36902

Hom.:

1997

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.454

Gnomad AMR

AF:

0.464

Gnomad ASJ

AF:

0.496

Gnomad EAS

AF:

0.449

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.636

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.471

Gnomad OTH

AF:

0.439

GnomAD4 exome

AF:

0.310

AC:

42257

AN:

136216

Hom.:

2465

AF XY:

0.304

AC XY:

21371

AN XY:

70376

show subpopulations

Gnomad4 AFR exome

AF:

0.162

Gnomad4 AMR exome

AF:

0.225

Gnomad4 ASJ exome

AF:

0.321

Gnomad4 EAS exome

AF:

0.319

Gnomad4 SAS exome

AF:

0.190

Gnomad4 FIN exome

AF:

0.288

Gnomad4 NFE exome

AF:

0.333

Gnomad4 OTH exome

AF:

0.298

GnomAD4 genome

AF:

0.423

AC:

15617

AN:

36894

Hom.:

1990

Cov.:

AF XY:

0.425

AC XY:

6885

AN XY:

16208

show subpopulations

Gnomad4 AFR

AF:

0.260

Gnomad4 AMR

AF:

0.463

Gnomad4 ASJ

AF:

0.496

Gnomad4 EAS

AF:

0.448

Gnomad4 SAS

AF:

0.403

Gnomad4 FIN

AF:

0.636

Gnomad4 NFE

AF:

0.471

Gnomad4 OTH

AF:

0.439

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

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)

0.060

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-GAAAAAAAAAAAAAAA

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