rs5848

Positions:

chr17-44352876-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002087.4(GRN):c.*78C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,404,270 control chromosomes in the GnomAD database, including 74,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 14595 hom., cov: 32)

Exomes 𝑓: 0.30 ( 59842 hom. )

Consequence

GRN
NM_002087.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: -0.491

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 17-44352876-C-T is Benign according to our data. Variant chr17-44352876-C-T is described in ClinVar as [Benign]. Clinvar id is 29742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4 linkuse as main transcript	c.*78C>T		3_prime_UTR_variant	13/13	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 linkuse as main transcript	c.*78C>T	3_prime_UTR_variant	13/13	1	NM_002087.4	ENSP00000053867	P1	P28799-1
GRN	ENST00000586242.1 linkuse as main transcript	c.*107C>T	3_prime_UTR_variant	3/3	3		ENSP00000467837
GRN	ENST00000586443.1 linkuse as main transcript	c.*224C>T	3_prime_UTR_variant	7/7	3		ENSP00000465673
GRN	ENST00000589265.5 linkuse as main transcript	c.*78C>T	3_prime_UTR_variant	9/9	5		ENSP00000467616

Frequencies

GnomAD3 genomes

AF:

0.405

AC:

61476

AN:

151802

Hom.:

14579

Cov.:

show subpopulations

Gnomad AFR

AF:

0.672

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.258

Gnomad ASJ

AF:

0.393

Gnomad EAS

AF:

0.354

Gnomad SAS

AF:

0.330

Gnomad FIN

AF:

0.363

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.373

GnomAD4 exome

AF:

0.300

AC:

375744

AN:

1252350

Hom.:

59842

Cov.:

AF XY:

0.300

AC XY:

188904

AN XY:

629802

show subpopulations

Gnomad4 AFR exome

AF:

0.679

Gnomad4 AMR exome

AF:

0.212

Gnomad4 ASJ exome

AF:

0.385

Gnomad4 EAS exome

AF:

0.312

Gnomad4 SAS exome

AF:

0.324

Gnomad4 FIN exome

AF:

0.350

Gnomad4 NFE exome

AF:

0.283

Gnomad4 OTH exome

AF:

0.326

GnomAD4 genome

AF:

0.405

AC:

61529

AN:

151920

Hom.:

14595

Cov.:

AF XY:

0.402

AC XY:

29882

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.672

Gnomad4 AMR

AF:

0.258

Gnomad4 ASJ

AF:

0.393

Gnomad4 EAS

AF:

0.353

Gnomad4 SAS

AF:

0.329

Gnomad4 FIN

AF:

0.363

Gnomad4 NFE

AF:

0.295

Gnomad4 OTH

AF:

0.370

Alfa

AF:

0.308

Hom.:

6688

Bravo

AF:

0.406

Asia WGS

AF:

0.354

AC:

1237

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is associated with the following publications: (PMID: 25239657, 24770881, 22505994, 21212639, 29653316, 28286146, 24499389, 18723524, 20197700, 21047645, 24680777, 19016491) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 15, 2024

- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Ischemic stroke

Other:1

Affects, no assertion criteria provided

case-control

Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University

- -

FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS, SUSCEPTIBILITY TO

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.2

DANN

Benign

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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