rs72824736

Positions:

• chr17-44351170-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000053867.8(GRN):​c.835+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0648 in 1,614,032 control chromosomes in the GnomAD database, including 4,152 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (250 hom., cov: 33)
  • Exomes 𝑓: 0.067 (3902 hom.)
• Consequence: GRN ENST00000053867.8 splice_region, intron
• Scores: Splicing: ADA: 0.0001328
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0320

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 (BayesDel_noAF=-0.88).
• BP6: Variant 17-44351170-G-A is Benign according to our data. Variant chr17-44351170-G-A is described in ClinVar as [Benign]. Clinvar id is 258553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44351170-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4	c.835+7G>A		splice_region_variant, intron_variant		ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.835+7G>A		splice_region_variant, intron_variant		1	NM_002087.4	ENSP00000053867	P1

Frequencies

GnomAD3 genomes AF: 0.0461 AC: 7013 AN: 152210 Hom.: 250 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0531

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0759

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0455 AC: 11432 AN: 251256 Hom.: 400 AF XY: 0.0451 AC XY: 6124 AN XY: 135804

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0771

Gnomad OTH exome AF: 0.0429

GnomAD4 exome AF: 0.0668 AC: 97640 AN: 1461704 Hom.: 3902 Cov.: 34 AF XY: 0.0645 AC XY: 46916 AN XY: 727164

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.0169

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.0574

Gnomad4 NFE exome AF: 0.0798

Gnomad4 OTH exome AF: 0.0542

GnomAD4 genome AF: 0.0460 AC: 7008 AN: 152328 Hom.: 250 Cov.: 33 AF XY: 0.0435 AC XY: 3237 AN XY: 74488

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.0255

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0531

Gnomad4 NFE AF: 0.0759

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0619 Hom.: 179

Bravo AF: 0.0423

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0
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: rs72824736; hg19: chr17-42428538;