rs63749905

Variant names:

• chr17-44351759-C-CA
• rs63749905
• NM_002087.4:c.1144dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002087.4(GRN):​c.1144dupA​(p.Thr382AsnfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T382T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRN NM_002087.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -7.83
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44351759-C-CA is Pathogenic according to our data. Variant chr17-44351759-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 98169.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4	c.1144dupA	p.Thr382AsnfsTer32	frameshift_variant	Exon 10 of 13	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.1144dupA	p.Thr382AsnfsTer32	frameshift_variant	Exon 10 of 13	1	NM_002087.4	ENSP00000053867.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Pathogenic:1

Oct 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 98169). This variant is also known as c.1145insA (p.Thr382AsnfsX31). This premature translational stop signal has been observed in individual(s) with frontotemporal dementia (PMID: 17620546). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr382Asnfs*32) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). -

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

Jul 10, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

-

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-7.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63749905; hg19: chr17-42429127;