17-44349572-G-A

Position:

• chr17-44349572-G-A

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.264+21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,613,786 control chromosomes in the GnomAD database, including 19,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4235 hom., cov: 33)
  • Exomes 𝑓: 0.13 (15627 hom.)
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.99

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=-0.89).
• BP6: Variant 17-44349572-G-A is Benign according to our data. Variant chr17-44349572-G-A is described in ClinVar as [Benign]. Clinvar id is 558916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44349572-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.264+21G>A		intron_variant		ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.264+21G>A		intron_variant		1	NM_002087.4	P1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30343 AN: 152128 Hom.: 4203 Cov.: 33

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0898

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.183

GnomAD3 exomes AF: 0.159 AC: 39920 AN: 250706 Hom.: 4216 AF XY: 0.163 AC XY: 22171 AN XY: 135782

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0924

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.131 AC: 190911 AN: 1461540 Hom.: 15627 Cov.: 34 AF XY: 0.135 AC XY: 98345 AN XY: 727118

Gnomad4 AFR exome AF: 0.405

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.0904

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.200 AC: 30424 AN: 152246 Hom.: 4235 Cov.: 33 AF XY: 0.201 AC XY: 14958 AN XY: 74456

Gnomad4 AFR AF: 0.392

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.0901

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.181

Alfa AF: 0.132 Hom.: 1484

Bravo AF: 0.203

Asia WGS AF: 0.241 AC: 838 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

Neuronal ceroid lipofuscinosis 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.019
DANN	Benign	0.46

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: rs9897526; hg19: chr17-42426940; COSMIC: COSV50010157; COSMIC: COSV50010157;