Genetic Variant C9orf72:c.1260-25_1260-14delTTTTTTTTTTTT (chr9-27548435-GAAAAAAAAAAAA-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_018325.5(C9orf72):c.1260-25_1260-14delTTTTTTTTTTTT variant causes a intron change. The variant allele was found at a frequency of 0.0019 in 174,882 control chromosomes in the GnomAD database, including 7 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00076 ( 2 hom., cov: 0)

Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

C9orf72
NM_018325.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.15

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0022 (304/138116) while in subpopulation MID AF = 0.0483 (26/538). AF 95% confidence interval is 0.0339. There are 5 homozygotes in GnomAdExome4. There are 158 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9orf72	NM_018325.5	MANE Select	c.1260-25_1260-14delTTTTTTTTTTTT		intron	N/A	NP_060795.1	Q96LT7-1
	C9orf72	NM_001256054.3		c.1260-25_1260-14delTTTTTTTTTTTT		intron	N/A	NP_001242983.1	Q96LT7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
C9orf72	ENST00000380003.8	TSL:1 MANE Select	c.1260-25_1260-14delTTTTTTTTTTTT	intron	N/A	ENSP00000369339.3	Q96LT7-1
C9orf72	ENST00000619707.5	TSL:1	c.1260-25_1260-14delTTTTTTTTTTTT	intron	N/A	ENSP00000482753.1	Q96LT7-1
C9orf72	ENST00000644136.1		c.1293-25_1293-14delTTTTTTTTTTTT	intron	N/A	ENSP00000494872.1	A0A2R8Y5K2

Frequencies

GnomAD3 genomes

AF:

0.000761

AC:

AN:

36774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00355

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0345

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00220

AC:

304

AN:

138116

Hom.:

AF XY:

0.00221

AC XY:

158

AN XY:

71376

show subpopulations

African (AFR)

AF:

0.00581

AC:

AN:

3096

American (AMR)

AF:

0.00442

AC:

AN:

5658

Ashkenazi Jewish (ASJ)

AF:

0.000805

AC:

AN:

3728

East Asian (EAS)

AF:

0.00

AC:

AN:

13460

South Asian (SAS)

AF:

0.000252

AC:

AN:

7942

European-Finnish (FIN)

AF:

0.000248

AC:

AN:

8070

Middle Eastern (MID)

AF:

0.0483

AC:

AN:

538

European-Non Finnish (NFE)

AF:

0.00233

AC:

207

AN:

88690

Other (OTH)

AF:

0.00303

AC:

AN:

6934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000762

AC:

AN:

36766

Hom.:

Cov.:

AF XY:

0.000868

AC XY:

AN XY:

16134

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

8168

American (AMR)

AF:

0.00355

AC:

AN:

3102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1360

East Asian (EAS)

AF:

0.00

AC:

AN:

1452

South Asian (SAS)

AF:

0.00140

AC:

AN:

714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

388

Middle Eastern (MID)

AF:

0.0200

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000677

AC:

AN:

20694

Other (OTH)

AF:

0.00

AC:

AN:

490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.706

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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9-27548435-GAAAAAAAAAAAAAAAAAA-GAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over