rs60100877

Positions:

Variant summary

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

The NM_002087.4(GRN):c.264+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 0.00612 in 1,614,116 control chromosomes in the GnomAD database, including 35 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0062 ( 31 hom. )

Consequence

GRN
NM_002087.4 splice_region, intron

Scores

Splicing: ADA: 0.0003705

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.972

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 17-44349558-G-A is Benign according to our data. Variant chr17-44349558-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44349558-G-A is described in Lovd as [Benign]. Variant chr17-44349558-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00551 (839/152338) while in subpopulation AMR AF= 0.00843 (129/15304). AF 95% confidence interval is 0.00725. There are 4 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4 link	c.264+7G>A		splice_region_variant, intron_variant		ENST00000053867.8	NP_002078.1	P28799-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 link	c.264+7G>A		splice_region_variant, intron_variant		1	NM_002087.4	ENSP00000053867.2		P28799-1

Frequencies

GnomAD3 genomes

AF:

0.00552

AC:

840

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00739

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00515

AC:

1291

AN:

250846

Hom.:

AF XY:

0.00522

AC XY:

709

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00489

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00277

Gnomad SAS exome

AF:

0.00284

Gnomad FIN exome

AF:

0.00481

Gnomad NFE exome

AF:

0.00691

Gnomad OTH exome

AF:

0.00670

GnomAD4 exome

AF:

0.00618

AC:

9038

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00615

AC XY:

4474

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00543

Gnomad4 ASJ exome

AF:

0.00325

Gnomad4 EAS exome

AF:

0.00166

Gnomad4 SAS exome

AF:

0.00235

Gnomad4 FIN exome

AF:

0.00465

Gnomad4 NFE exome

AF:

0.00694

Gnomad4 OTH exome

AF:

0.00596

GnomAD4 genome

AF:

0.00551

AC:

839

AN:

152338

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00843

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00309

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00499

Gnomad4 NFE

AF:

0.00739

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00503

Hom.:

Bravo

AF:

0.00623

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00936

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	GRN: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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). No publications were found based on this search. Allele frequency data from public databases allowed determination 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	- -

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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.6

DANN

Benign

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00037

dbscSNV1_RF

Benign

0.0

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

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