rs63750412

chr17-44352132-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.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 NM_002087.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.819

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=0.0036028922).
• 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 GnomAd at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.1297C>T	p.Arg433Trp	missense_variant	11/13	ENST00000053867.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152154 Hom.: 11 Cov.: 33

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.: 22 AF XY: 0.00536 AC XY: 729 AN XY: 135884

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.: 58 Cov.: 33 AF XY: 0.00394 AC XY: 2867 AN XY: 727122

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.: 11 Cov.: 33 AF XY: 0.00661 AC XY: 492 AN XY: 74468

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.: 0

Bravo AF: 0.00175

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00432 AC: 524

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GRN: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 07, 2015	- -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
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	T
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

Other links and lift over

dbSNP: rs63750412; hg19: chr17-42429500; COSMIC: COSV50007726; COSMIC: COSV50007726;