rs63750043

Positions:

chr17-44350237-C-A

Variant summary

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

The NM_002087.4(GRN):c.359C>A(p.Ser120Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,612,426 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 8 hom. )

Consequence

GRN
NM_002087.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3B:7O:1

Conservation

PhyloP100: -0.172

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=0.0062176883).

BP6

Variant 17-44350237-C-A is Benign according to our data. Variant chr17-44350237-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 98135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44350237-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000755 (115/152228) while in subpopulation AMR AF= 0.00314 (48/15304). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4 linkuse as main transcript	c.359C>A	p.Ser120Tyr	missense_variant	5/13	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.359C>A	p.Ser120Tyr	missense_variant	5/13	1	NM_002087.4	ENSP00000053867	P1	P28799-1

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.00105

AC:

265

AN:

251464

Hom.:

AF XY:

0.00134

AC XY:

182

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000527

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.000652

AC:

952

AN:

1460198

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

576

AN XY:

726558

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00328

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000321

Gnomad4 OTH exome

AF:

0.00143

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152228

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000743

Hom.:

Bravo

AF:

0.000612

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:3Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:4Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GRN: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2017	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	This variant is associated with the following publications: (PMID: 31996268, 32507413, 18328591, 29956270, 27997711, 22781549, 20020531, 26075876, 27884173, 17371905, 18245784, 19632744) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2019

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.39

CADD

Benign

2.1

DANN

Benign

0.84

DEOGEN2

Benign

0.21

T;.;T;.;T;T;T;T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.73

T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.0062

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

2.0

M;.;.;.;.;.;.;.;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.2

N;.;.;.;.;.;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.16

T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.11

T;T;T;T;T;T;T;T;.

Polyphen

0.74

P;.;.;.;.;.;.;.;.

Vest4

0.29

MVP

0.86

MPC

0.46

ClinPred

0.0077

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.052

gMVP

0.28

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