rs17523519

Variant names:

• chr17-44345007-TC-T
• rs17523519
• ENST00000588170.5:n.-238delC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000588170.5(GRN):​n.-238delC variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,772 control chromosomes in the GnomAD database, including 13,725 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (13724 hom., cov: 0)
  • Exomes 𝑓: 0.24 (1 hom.)
• Consequence: GRN ENST00000588170.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000588170.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	ENST00000588170.5	TSL:2	n.-238delC		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60243 AN: 151584 Hom.: 13684 Cov.: 0

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.895

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.243 AC: 17 AN: 70 Hom.: 1 AF XY: 0.227 AC XY: 10 AN XY: 44

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.500 AC: 3 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.233 AC: 14 AN: 60

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000411960), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.398 AC: 60339 AN: 151702 Hom.: 13724 Cov.: 0 AF XY: 0.409 AC XY: 30313 AN XY: 74126

African (AFR) AF: 0.528 AC: 21828 AN: 41334

American (AMR) AF: 0.441 AC: 6718 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 835 AN: 3464

East Asian (EAS) AF: 0.895 AC: 4635 AN: 5178

South Asian (SAS) AF: 0.481 AC: 2318 AN: 4816

European-Finnish (FIN) AF: 0.398 AC: 4178 AN: 10508

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.276 AC: 18738 AN: 67856

Other (OTH) AF: 0.374 AC: 786 AN: 2104

Alfa AF: 0.332 Hom.: 1120

Bravo AF: 0.409

Asia WGS AF: 0.690 AC: 2398 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.22

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17523519; hg19: chr17-42422375;