rs63751294

Positions:

chr17-44352404-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_002087.4(GRN):c.1477C>T(p.Arg493Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

GRN
NM_002087.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:2

Conservation

PhyloP100: 0.481

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-44352404-C-T is Pathogenic according to our data. Variant chr17-44352404-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44352404-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4 linkuse as main transcript	c.1477C>T	p.Arg493Ter	stop_gained	12/13	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.1477C>T	p.Arg493Ter	stop_gained	12/13	1	NM_002087.4	ENSP00000053867	P1	P28799-1
GRN	ENST00000589265.5 linkuse as main transcript	c.1006C>T	p.Arg336Ter	stop_gained	8/9	5		ENSP00000467616
GRN	ENST00000586443.1 linkuse as main transcript	c.919C>T	p.Arg307Ter	stop_gained	7/7	3		ENSP00000465673
GRN	ENST00000586242.1 linkuse as main transcript	c.112C>T	p.Arg38Ter	stop_gained	2/3	3		ENSP00000467837

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251110

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461638

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; One of the most common variants reported in the GRN gene in individuals with frontotemporal dementia (Gass et al., 2006; Huey et al., 2006; Rademakers et al., 2007); Published functional studies demonstrate a damaging effect (Fujita et al., 2018); This variant is associated with the following publications: (PMID: 16983677, 28473694, 21482928, 24703252, 22608501, 26791154, 27341800, 28304311, 29080331, 16950801, 17826340, 17522386, 28404863, 22312439, 18703462, 17210807, 17071927, 17345602, 29382817, 30279455, 31031559, 29511098, 29724592, 29146050, 30696728, 31361008, 31996268, 30924900, 33351065) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 20, 2017	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 21, 2022	- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Aug 31, 2021	Criteria Codes: PVS1 PS3 PS4_Mod PM2_Supp PP1 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2011	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

GRN-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2024

The GRN c.1477C>T variant is predicted to result in premature protein termination (p.Arg493*). This variant has been reported to be pathogenic for frontotemporal lobar degeneration (Gass et al. 2006. PubMed ID: 16950801; Rademakers et al. 2007. PubMed ID: 17826340; Huey et al. 2006. PubMed ID: 16983677). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Nonsense variants in GRN are expected to be pathogenic and this variant has been consistently classified as pathogenic in ClinVar. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

This sequence change creates a premature translational stop signal (p.Arg493*) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). This variant is present in population databases (rs63751294, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with frontotemporal dementia and primary progressive aphasia (PMID: 16950801, 26791154, 30279455). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16014). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Benign

-0.0022

FATHMM_MKL

Benign

0.17

MutationTaster

Benign

1.0

A;A

Vest4

0.89

GERP RS

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

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

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