Genetic Variant GRN:c.-8+854C>T (chr17-44346188-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002087.4(GRN):c.-8+854C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 154,108 control chromosomes in the GnomAD database, including 6,409 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6284 hom., cov: 32)

Exomes 𝑓: 0.32 ( 125 hom. )

Consequence

GRN
NM_002087.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.620

Publications

10 publications found

Variant links:

Genes affected

GRN (HGNC:4601): (granulin precursor) Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and PC cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis. [provided by RefSeq, Jul 2008]

GRN Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
neuronal ceroid lipofuscinosis 11
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P, Orphanet

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4 link	c.-8+854C>T		intron_variant	Intron 1 of 12	ENST00000053867.8	NP_002078.1	P28799-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 link	c.-8+854C>T		intron_variant	Intron 1 of 12	1	NM_002087.4	ENSP00000053867.2		P28799-1

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42115

AN:

151948

Hom.:

6280

Cov.:

show subpopulations

Gnomad AFR

AF:

0.233

Gnomad AMI

AF:

0.209

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.583

Gnomad SAS

AF:

0.430

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.258

GnomAD4 exome

AF:

0.322

AC:

657

AN:

2042

Hom.:

125

Cov.:

AF XY:

0.315

AC XY:

354

AN XY:

1124

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.393

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.260

AC:

AN:

East Asian (EAS)

AF:

0.660

AC:

165

AN:

250

South Asian (SAS)

AF:

0.563

AC:

AN:

European-Finnish (FIN)

AF:

0.367

AC:

105

AN:

286

Middle Eastern (MID)

AF:

0.214

AC:

AN:

European-Non Finnish (NFE)

AF:

0.252

AC:

316

AN:

1254

Other (OTH)

AF:

0.240

AC:

AN:

104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.277

AC:

42131

AN:

152066

Hom.:

6284

Cov.:

AF XY:

0.287

AC XY:

21298

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.233

AC:

9685

AN:

41510

American (AMR)

AF:

0.309

AC:

4718

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

822

AN:

3466

East Asian (EAS)

AF:

0.584

AC:

3012

AN:

5160

South Asian (SAS)

AF:

0.429

AC:

2061

AN:

4808

European-Finnish (FIN)

AF:

0.328

AC:

3469

AN:

10574

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.259

AC:

17566

AN:

67944

Other (OTH)

AF:

0.258

AC:

544

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1509

3018

4527

6036

7545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.154

Hom.:

324

Bravo

AF:

0.273

Asia WGS

AF:

0.492

AC:

1710

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.1

(source)

DANN

Benign

0.94

PhyloP100

-0.62

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over