rs60100877

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
neuronal ceroid lipofuscinosis 11
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P, Orphanet

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 196337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4 link	c.264+7G>A		splice_region_variant, intron_variant	Intron 3 of 12	ENST00000053867.8	NP_002078.1	P28799-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 link	c.264+7G>A		splice_region_variant, intron_variant	Intron 3 of 12	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

GnomAD2 exomes

AF:

0.00515

AC:

1291

AN:

250846

AF XY:

0.00522

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 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

African (AFR)

AF:

0.00182

AC:

AN:

33480

American (AMR)

AF:

0.00543

AC:

243

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00325

AC:

AN:

26134

East Asian (EAS)

AF:

0.00166

AC:

AN:

39700

South Asian (SAS)

AF:

0.00235

AC:

203

AN:

86258

European-Finnish (FIN)

AF:

0.00465

AC:

248

AN:

53344

Middle Eastern (MID)

AF:

0.00919

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00694

AC:

7719

AN:

1111976

Other (OTH)

AF:

0.00596

AC:

360

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

539

1078

1617

2156

2695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

284

568

852

1136

1420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00551

AC:

839

AN:

152338

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41570

American (AMR)

AF:

0.00843

AC:

129

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00309

AC:

AN:

5182

South Asian (SAS)

AF:

0.00269

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00739

AC:

503

AN:

68034

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jan 22, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GRN: BP4, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Oct 28, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 23, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.6

(source)

DANN

Benign

0.66

PhyloP100

0.97

PromoterAI

0.0022

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over