rs63750723

chr17-44349219-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.478

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 Benign. Variant got -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 id is 98120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44349219-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.55C>T	p.Arg19Trp	missense_variant	2/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.55C>T	p.Arg19Trp	missense_variant	2/13	1	NM_002087.4	P1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1841 AN: 152214 Hom.: 47 Cov.: 33

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

GnomAD3 exomes AF: 0.00352 AC: 885 AN: 251208 Hom.: 17 AF XY: 0.00257 AC XY: 349 AN XY: 135848

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 SAS exome AF: 0.000196

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.: 27 Cov.: 34 AF XY: 0.00114 AC XY: 832 AN XY: 727152

Gnomad4 AFR exome AF: 0.0435

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.0121 AC: 1848 AN: 152332 Hom.: 46 Cov.: 33 AF XY: 0.0117 AC XY: 868 AN XY: 74506

Gnomad4 AFR AF: 0.0423

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00320 Hom.: 8

Bravo AF: 0.0140

ESP6500AA AF: 0.0477 AC: 210

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00419 AC: 509

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 2020	This variant is associated with the following publications: (PMID: 30530974) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 20, 2017	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2016

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

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	14
Dann	Benign	0.91
DEOGEN2	Benign	0.23	T;.;T;.;T;.;.;T;T;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.66	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.;.;.;.;.;.;.;.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.1	N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.088	T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0030	B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.23
MVP		0.64
MPC		0.24
ClinPred		0.012	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.49

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: rs63750723; hg19: chr17-42426587; COSMIC: COSV99029744; COSMIC: COSV99029744;