NM_002087.4:c.-8+963A>G

Variant names:

• chr17-44346297-A-G
• rs3785817
• NM_002087.4:c.-8+963A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002087.4(GRN):​c.-8+963A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,082 control chromosomes in the GnomAD database, including 6,625 homozygotes. 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 0.29 (6612 hom., cov: 31)
  • Exomes 𝑓: 0.31 (13 hom.)
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	NM_002087.4	MANE Select	c.-8+963A>G		intron	N/A	NP_002078.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	ENST00000053867.8	TSL:1 MANE Select	c.-8+963A>G		intron	N/A	ENSP00000053867.2
	GRN	ENST00000589265.5	TSL:5	c.-8+963A>G		intron	N/A	ENSP00000467616.1
	GRN	ENST00000587387.5	TSL:4	c.-8+963A>G		intron	N/A	ENSP00000467431.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43338 AN: 151802 Hom.: 6609 Cov.: 31

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.263

GnomAD4 exome AF: 0.315 AC: 51 AN: 162 Hom.: 13 AF XY: 0.260 AC XY: 27 AN XY: 104

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 3 AN: 6

East Asian (EAS) AF: 0.714 AC: 10 AN: 14

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 9 AN: 18

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.226 AC: 24 AN: 106

Other (OTH) AF: 0.375 AC: 3 AN: 8

GnomAD4 genome AF: 0.285 AC: 43352 AN: 151920 Hom.: 6612 Cov.: 31 AF XY: 0.295 AC XY: 21872 AN XY: 74240

African (AFR) AF: 0.239 AC: 9909 AN: 41412

American (AMR) AF: 0.313 AC: 4772 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3472

East Asian (EAS) AF: 0.587 AC: 3019 AN: 5140

South Asian (SAS) AF: 0.423 AC: 2034 AN: 4810

European-Finnish (FIN) AF: 0.350 AC: 3695 AN: 10564

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18288 AN: 67944

Other (OTH) AF: 0.263 AC: 555 AN: 2112

Alfa AF: 0.276 Hom.: 24125

Bravo AF: 0.280

Asia WGS AF: 0.486 AC: 1686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.83
PhyloP100		-0.79
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: rs3785817; hg19: chr17-42423665;