rs63750412

Positions:

chr17-44352132-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000053867.8(GRN):c.1297C>T(p.Arg433Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,822 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R433Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0050 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 58 hom. )

Consequence

GRN
ENST00000053867.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 0.819

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036028922).

BP6

Variant 17-44352132-C-T is Benign according to our data. Variant chr17-44352132-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 98180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44352132-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.005 (761/152272) while in subpopulation NFE AF= 0.00338 (230/68004). AF 95% confidence interval is 0.00302. There are 11 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4 linkuse as main transcript	c.1297C>T	p.Arg433Trp	missense_variant	11/13	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 linkuse as main transcript	c.1297C>T	p.Arg433Trp	missense_variant	11/13	1	NM_002087.4	ENSP00000053867	P1	P28799-1
GRN	ENST00000589265.5 linkuse as main transcript	c.826C>T	p.Arg276Trp	missense_variant	7/9	5		ENSP00000467616
GRN	ENST00000586443.1 linkuse as main transcript	c.739C>T	p.Arg247Trp	missense_variant	6/7	3		ENSP00000465673

Frequencies

GnomAD3 genomes

AF:

0.00500

AC:

761

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0438

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00338

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00548

AC:

1377

AN:

251108

Hom.:

AF XY:

0.00536

AC XY:

729

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.000994

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.0404

Gnomad NFE exome

AF:

0.00323

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00408

AC:

5958

AN:

1461550

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

2867

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.0370

Gnomad4 NFE exome

AF:

0.00318

Gnomad4 OTH exome

AF:

0.00335

GnomAD4 genome

AF:

0.00500

AC:

761

AN:

152272

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

492

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0438

Gnomad4 NFE

AF:

0.00338

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00279

Hom.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00432

AC:

524

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GRN: BP4, BS1, BS2 -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2019	- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2017	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.7

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.3

N;.

REVEL

Benign

0.22

Sift

Uncertain

0.018

D;.

Sift4G

Uncertain

0.017

D;D

Polyphen

0.95

P;.

Vest4

0.30

MVP

0.90

MPC

0.48

ClinPred

0.017

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

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