rs63750043

chr17-44350237-C-A

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.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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S120S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (8 hom.)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:3 B:6 O:1
• Conservation: PhyloP100: -0.172

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=0.0062176883).
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.359C>A	p.Ser120Tyr	missense_variant	5/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.359C>A	p.Ser120Tyr	missense_variant	5/13	1	NM_002087.4	P1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152110 Hom.: 0 Cov.: 32

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.: 3 AF XY: 0.00134 AC XY: 182 AN XY: 135910

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.: 8 Cov.: 34 AF XY: 0.000793 AC XY: 576 AN XY: 726558

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.: 0 Cov.: 32 AF XY: 0.000847 AC XY: 63 AN XY: 74420

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.: 5

Bravo AF: 0.000612

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000824 AC: 100

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:3 Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3 Benign:3 Other: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	-	- -
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) -
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 -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2017	- -

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

Invitae

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	T
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	N
LIST_S2	Benign	0.73	T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0062	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

dbSNP: rs63750043; hg19: chr17-42427605;