rs25647

chr17-44352471-G-Cchr17-44352471-G-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.1544G>C(p.Gly515Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,614,046 control chromosomes in the GnomAD database, including 43 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: GRN NM_002087.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -1.05

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=0.0036056936).
• BP6: Variant 17-44352471-G-C is Benign according to our data. Variant chr17-44352471-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 98189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44352471-G-C is described in Lovd as [Likely_benign]. Variant chr17-44352471-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00798 (1216/152312) while in subpopulation AFR AF= 0.0269 (1117/41568). AF 95% confidence interval is 0.0256. There are 20 homozygotes in gnomad4. There are 569 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.1544G>C	p.Gly515Ala	missense_variant	12/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.1544G>C	p.Gly515Ala	missense_variant	12/13	1	NM_002087.4	P1
GRN	ENST00000589265.5	c.1073G>C	p.Gly358Ala	missense_variant	8/9	5
GRN	ENST00000586443.1	c.986G>C	p.Gly329Ala	missense_variant	7/7	3
GRN	ENST00000586242.1	c.179G>C	p.Gly60Ala	missense_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 1206 AN: 152194 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00225 AC: 565 AN: 251388 Hom.: 6 AF XY: 0.00178 AC XY: 242 AN XY: 135898

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00106 AC: 1553 AN: 1461734 Hom.: 23 Cov.: 34 AF XY: 0.000934 AC XY: 679 AN XY: 727172

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000224

Gnomad4 OTH exome AF: 0.00311

GnomAD4 genome AF: 0.00798 AC: 1216 AN: 152312 Hom.: 20 Cov.: 33 AF XY: 0.00764 AC XY: 569 AN XY: 74498

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00112 Hom.: 1

Bravo AF: 0.00921

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0297 AC: 131

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely 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	GeneDx	Mar 06, 2020	This variant is associated with the following publications: (PMID: 22312439, 23759146, 27884173, 18565828) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	GRN: BP4, BS1, BS2 -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 25, 2021	- -

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 23, 2017	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.83
Dann	Benign	0.85
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.10
Sift	Benign	0.14	T;.
Sift4G	Benign	0.56	T;T
Polyphen		0.50	P;.
Vest4		0.18
MVP		0.82
MPC		0.25
ClinPred		0.014	T
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.057
gMVP		0.61

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: rs25647; hg19: chr17-42429839;