17-44349167-G-A

Position:

• chr17-44349167-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_002087.4(GRN):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRN NM_002087.4 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.67

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_002087.4 (GRN) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44349167-G-A is Pathogenic according to our data. Variant chr17-44349167-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16009.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-44349167-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRN	NM_002087.4	c.3G>A	p.Met1?	start_lost	2/13	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.3G>A	p.Met1?	start_lost	2/13	1	NM_002087.4	ENSP00000053867	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 24, 2006

- -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T;.;T;.;.;T;T;T;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationTaster	Benign	1.0	A;A
PROVEAN	Benign	-1.9	N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.010	D;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.024	D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.80		Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);Loss of solvent accessibility (P = 0.0015);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs63750331; hg19: chr17-42426535;