chr17-44346188-C-T

Position:

• chr17-44346188-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002087.4(GRN):​c.-8+854C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 154,108 control chromosomes in the GnomAD database, including 6,409 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 0.28 (6284 hom., cov: 32)
  • Exomes 𝑓: 0.32 (125 hom.)
• Consequence: GRN NM_002087.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.620

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRN	NM_002087.4	c.-8+854C>T		intron_variant		ENST00000053867.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRN	ENST00000053867.8	c.-8+854C>T		intron_variant		1	NM_002087.4	P1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42115 AN: 151948 Hom.: 6280 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.258

GnomAD4 exome AF: 0.322 AC: 657 AN: 2042 Hom.: 125 Cov.: 0 AF XY: 0.315 AC XY: 354 AN XY: 1124

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.660

Gnomad4 SAS exome AF: 0.563

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.277 AC: 42131 AN: 152066 Hom.: 6284 Cov.: 32 AF XY: 0.287 AC XY: 21298 AN XY: 74324

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.584

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.258

Alfa AF: 0.151 Hom.: 308

Bravo AF: 0.273

Asia WGS AF: 0.492 AC: 1710 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.1
DANN	Benign	0.94

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: rs2879096; hg19: chr17-42423556;