rs4792939

Variant names:

• chr17-44347945-G-A
• rs4792939
• NM_002087.4:c.-7-1213G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002087.4(GRN):​c.-7-1213G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (11796 hom., cov: 16)
  • Failed GnomAD Quality Control
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 6 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	NM_002087.4	MANE Select	c.-7-1213G>A		intron	N/A	NP_002078.1	P28799-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	ENST00000053867.8	TSL:1 MANE Select	c.-7-1213G>A		intron	N/A	ENSP00000053867.2	P28799-1
	GRN	ENST00000900927.1		c.-28-1192G>A		intron	N/A	ENSP00000570986.1
	GRN	ENST00000900929.1		c.-8+514G>A		intron	N/A	ENSP00000570988.1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 54354 AN: 95818 Hom.: 11799 Cov.: 16

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.620

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.575

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.567 AC: 54353 AN: 95888 Hom.: 11796 Cov.: 16 AF XY: 0.565 AC XY: 25671 AN XY: 45460

African (AFR) AF: 0.448 AC: 11985 AN: 26730

American (AMR) AF: 0.544 AC: 4573 AN: 8412

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 1551 AN: 2500

East Asian (EAS) AF: 0.190 AC: 192 AN: 1010

South Asian (SAS) AF: 0.550 AC: 1224 AN: 2224

European-Finnish (FIN) AF: 0.634 AC: 3607 AN: 5692

Middle Eastern (MID) AF: 0.568 AC: 100 AN: 176

European-Non Finnish (NFE) AF: 0.636 AC: 30036 AN: 47252

Other (OTH) AF: 0.570 AC: 769 AN: 1350

Alfa AF: 0.797 Hom.: 50939

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.43
DANN	Benign	0.21
PhyloP100		0.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4792939;

hg19: chr17-42425313;

COSMIC: COSV50007835;

COSMIC: COSV50007835;