rs63750723

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002087.4(GRN):c.55C>T(p.Arg19Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,614,000 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 46 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 27 hom. )

Consequence

GRN
NM_002087.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.478

Publications

14 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), G2P, Ambry Genetics, Genomics England PanelApp, Orphanet

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004250467).

BP6

Variant 17-44349219-C-T is Benign according to our data. Variant chr17-44349219-C-T is described in ClinVar as Benign. ClinVar VariationId is 98120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1848/152332) while in subpopulation AFR AF = 0.0423 (1757/41566). AF 95% confidence interval is 0.0406. There are 46 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 46 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002087.4. 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
	GRN	NM_002087.4	MANE Select	c.55C>T	p.Arg19Trp	missense	Exon 2 of 13	NP_002078.1	P28799-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRN	ENST00000053867.8	TSL:1 MANE Select	c.55C>T	p.Arg19Trp	missense	Exon 2 of 13	ENSP00000053867.2	P28799-1
GRN	ENST00000900927.1		c.55C>T	p.Arg19Trp	missense	Exon 2 of 13	ENSP00000570986.1
GRN	ENST00000900929.1		c.55C>T	p.Arg19Trp	missense	Exon 3 of 14	ENSP00000570988.1

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1841

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0422

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00352

AC:

885

AN:

251208

AF XY:

0.00257

show subpopulations

Gnomad AFR exome

AF:

0.0468

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00131

AC:

1909

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

832

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.0435

AC:

1458

AN:

33480

American (AMR)

AF:

0.00284

AC:

127

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000106

AC:

118

AN:

1111922

Other (OTH)

AF:

0.00286

AC:

173

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

132

264

395

527

659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.0121

AC:

1848

AN:

152332

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

868

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0423

AC:

1757

AN:

41566

American (AMR)

AF:

0.00327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68024

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00622

Hom.:

Bravo

AF:

0.0140

ESP6500AA

AF:

0.0477

AC:

210

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00419

AC:

509

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (4)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (1)

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.23

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.48

PrimateAI

Benign

0.21

PROVEAN

Benign

-2.1

REVEL

Benign

0.14

Sift

Benign

0.088

Sift4G

Benign

0.11

Polyphen

0.0030

Vest4

0.23

MVP

0.64

MPC

0.24

ClinPred

0.012

GERP RS

2.7

PromoterAI

-0.00010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.49

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over