rs3785817

Positions:

• chr17-44346297-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4	c.-8+963A>G		intron_variant		ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.-8+963A>G		intron_variant		1	NM_002087.4	ENSP00000053867.2

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

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.375

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

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.587

Gnomad4 SAS AF: 0.423

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.263

Alfa AF: 0.270 Hom.: 9313

Bravo AF: 0.280

Asia WGS AF: 0.486 AC: 1686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.83

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: rs3785817; hg19: chr17-42423665;