rs850713

Variant names:

• chr17-44350364-G-A
• rs850713
• NM_002087.4:c.462+24G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-44350364-G-A
• chr17-44350364-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002087.4(GRN):​c.462+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,602,776 control chromosomes in the GnomAD database, including 52,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6050 hom., cov: 25)
  • Exomes 𝑓: 0.25 (46445 hom.)
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.981
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-44350364-G-A is Benign according to our data. Variant chr17-44350364-G-A is described in ClinVar as Benign. ClinVar VariationId is 558917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4	c.462+24G>A		intron_variant	Intron 5 of 12	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.462+24G>A		intron_variant	Intron 5 of 12	1	NM_002087.4	ENSP00000053867.2

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41338 AN: 149572 Hom.: 6049 Cov.: 25

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.281 AC: 70539 AN: 250930 AF XY: 0.282

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.492

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.246 AC: 357114 AN: 1453084 Hom.: 46445 Cov.: 33 AF XY: 0.248 AC XY: 179720 AN XY: 723452

African (AFR) AF: 0.318 AC: 10608 AN: 33340

American (AMR) AF: 0.224 AC: 10007 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 9334 AN: 26078

East Asian (EAS) AF: 0.505 AC: 20017 AN: 39652

South Asian (SAS) AF: 0.314 AC: 27022 AN: 86104

European-Finnish (FIN) AF: 0.301 AC: 16041 AN: 53272

Middle Eastern (MID) AF: 0.323 AC: 1861 AN: 5754

European-Non Finnish (NFE) AF: 0.223 AC: 246065 AN: 1104084

Other (OTH) AF: 0.269 AC: 16159 AN: 60094

GnomAD4 genome AF: 0.276 AC: 41346 AN: 149692 Hom.: 6050 Cov.: 25 AF XY: 0.278 AC XY: 20311 AN XY: 72962

African (AFR) AF: 0.327 AC: 13264 AN: 40578

American (AMR) AF: 0.233 AC: 3520 AN: 15106

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1224 AN: 3456

East Asian (EAS) AF: 0.490 AC: 2423 AN: 4948

South Asian (SAS) AF: 0.323 AC: 1515 AN: 4686

European-Finnish (FIN) AF: 0.299 AC: 3081 AN: 10308

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15500 AN: 67332

Other (OTH) AF: 0.276 AC: 574 AN: 2080

Alfa AF: 0.254 Hom.: 963

Bravo AF: 0.274

Asia WGS AF: 0.388 AC: 1354 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.68
PhyloP100		-0.98
PromoterAI		0.0090	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs850713; hg19: chr17-42427732; COSMIC: COSV50006138; COSMIC: COSV50006138;