chr17-44352876-C-T

Variant names:

• chr17-44352876-C-T
• rs5848
• NM_002087.4:c.*78C>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.*78C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,404,270 control chromosomes in the GnomAD database, including 74,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14595 hom., cov: 32)
  • Exomes 𝑓: 0.30 (59842 hom.)
• Consequence: GRN NM_002087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: -0.491
• Publications: 231 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=-0.81).
• BP6: Variant 17-44352876-C-T is Benign according to our data. Variant chr17-44352876-C-T is described in ClinVar as Benign. ClinVar VariationId is 29742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.666 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	NM_002087.4	MANE Select	c.*78C>T		3_prime_UTR	Exon 13 of 13	NP_002078.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRN	ENST00000053867.8	TSL:1 MANE Select	c.*78C>T		3_prime_UTR	Exon 13 of 13	ENSP00000053867.2
	GRN	ENST00000900927.1		c.*78C>T		3_prime_UTR	Exon 13 of 13	ENSP00000570986.1
	GRN	ENST00000900929.1		c.*78C>T		3_prime_UTR	Exon 14 of 14	ENSP00000570988.1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61476 AN: 151802 Hom.: 14579 Cov.: 32

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.373

GnomAD4 exome AF: 0.300 AC: 375744 AN: 1252350 Hom.: 59842 Cov.: 18 AF XY: 0.300 AC XY: 188904 AN XY: 629802

African (AFR) AF: 0.679 AC: 20145 AN: 29670

American (AMR) AF: 0.212 AC: 8610 AN: 40678

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 9448 AN: 24548

East Asian (EAS) AF: 0.312 AC: 11715 AN: 37548

South Asian (SAS) AF: 0.324 AC: 26082 AN: 80378

European-Finnish (FIN) AF: 0.350 AC: 13283 AN: 37950

Middle Eastern (MID) AF: 0.352 AC: 1770 AN: 5022

European-Non Finnish (NFE) AF: 0.283 AC: 267191 AN: 942898

Other (OTH) AF: 0.326 AC: 17500 AN: 53658

GnomAD4 genome AF: 0.405 AC: 61529 AN: 151920 Hom.: 14595 Cov.: 32 AF XY: 0.402 AC XY: 29882 AN XY: 74260

African (AFR) AF: 0.672 AC: 27848 AN: 41432

American (AMR) AF: 0.258 AC: 3937 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1364 AN: 3472

East Asian (EAS) AF: 0.353 AC: 1815 AN: 5146

South Asian (SAS) AF: 0.329 AC: 1584 AN: 4816

European-Finnish (FIN) AF: 0.363 AC: 3834 AN: 10564

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.295 AC: 20024 AN: 67892

Other (OTH) AF: 0.370 AC: 782 AN: 2112

Alfa AF: 0.321 Hom.: 9707

Bravo AF: 0.406

Asia WGS AF: 0.354 AC: 1237 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (1)
-	-	1	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 (1)
-	-	-	FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS, SUSCEPTIBILITY TO (1)
-	-	-	Ischemic stroke (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.2
DANN	Benign	0.77
PhyloP100		-0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5848; hg19: chr17-42430244; COSMIC: COSV50006781; COSMIC: COSV50006781;