17-44352087-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_002087.4(GRN):c.1252C>T(p.Arg418Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,628 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: 0.0000048 (0 hom.)
• Consequence: GRN NM_002087.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: -1.14

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]

ACMG classification

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 17-44352087-C-T is Pathogenic according to our data. Variant chr17-44352087-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 98177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44352087-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.1252C>T	p.Arg418Ter	stop_gained	11/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.1252C>T	p.Arg418Ter	stop_gained	11/13	1	NM_002087.4	P1
GRN	ENST00000589265.5	c.781C>T	p.Arg261Ter	stop_gained	7/9	5
GRN	ENST00000586443.1	c.694C>T	p.Arg232Ter	stop_gained	6/7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461628 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 01, 2022	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2023

This sequence change creates a premature translational stop signal (p.Arg418*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with frontotemporal dementia (PMID: 16862116). ClinVar contains an entry for this variant (Variation ID: 98177). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Amyotrophic lateral sclerosis type 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Oct 04, 2022

ACMG criteria used to clasify this variant: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	26
Dann	Benign	0.78
Eigen	Benign	-0.57
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.065	N
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		-9.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs63751180; hg19: chr17-42429455; COSMIC: COSV105841424; COSMIC: COSV105841424;