rs5848

chr17-44352876-C-T

Variant summary

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

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: -0.491

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=-0.81).
• 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	UniProt
GRN	NM_002087.4	c.*78C>T		3_prime_UTR_variant	13/13	ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.*78C>T		3_prime_UTR_variant	13/13	1	NM_002087.4	P1
GRN	ENST00000586242.1	c.*107C>T		3_prime_UTR_variant	3/3	3
GRN	ENST00000586443.1	c.*224C>T		3_prime_UTR_variant	7/7	3
GRN	ENST00000589265.5	c.*78C>T		3_prime_UTR_variant	9/9	5

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61476 AN: 151802 Hom.: 14579 Cov.: 32

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.: 18 AF XY: 0.300 AC XY: 188904 AN XY: 629802

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.: 32 AF XY: 0.402 AC XY: 29882 AN XY: 74260

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:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

not provided Benign:1

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) -

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

Other links and lift over

dbSNP: rs5848; hg19: chr17-42430244; COSMIC: COSV50006781; COSMIC: COSV50006781;