rs778599933

Variant names:

• chr17-44350800-CGTGA-C
• rs778599933
• NM_002087.4:c.708+6_708+9delTGAG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The ENST00000053867.8(GRN):​c.708+1_708+4delGTGA variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,453,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: GRN ENST00000053867.8 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.22

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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.061728396 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 0 (no position change), new splice context is: aacGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 17-44350800-CGTGA-C is Pathogenic according to our data. Variant chr17-44350800-CGTGA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 586221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRN	NM_002087.4	c.708+6_708+9delTGAG		splice_region_variant, intron_variant	Intron 7 of 12	ENST00000053867.8	NP_002078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8	c.708+1_708+4delGTGA		splice_donor_variant, splice_region_variant, intron_variant	Intron 7 of 12	1	NM_002087.4	ENSP00000053867.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250578 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 41 AN: 1453738 Hom.: 0 AF XY: 0.0000221 AC XY: 16 AN XY: 723766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000362

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2018

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a patient with Alzheimers disease; however, no further clinical information was provided (Guven et al., 2016); Published functional studies demonstrate that the variant causes aberrant RNA splicing and reduction in PGRN mRNA, most likely through NMD of the mutant mRNA (Skoglund et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31914217, 20975516, 30475763, 30739198, 27859661, 24709683, 29256051, 32742620, 36264717, 27632209) -

Inborn genetic diseases Pathogenic:1

Sep 24, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.708+6_708+9delTGAG intronic variant, located in intron 6 of the GRN gene, results from a deletion of 4 nucleotides within intron 6 of the GRN gene. This variant was detected in two individuals with frontotemporal lobular degeneration (FTLD) with ubiquitin positive inclusions; analysis in one individual demonstrated a reduction in mRNA levels (83% of wild type) and aberrant splicing (Skoglund L et al. Alzheimer Dis Assoc Disord;25:173-8). In a second study, mRNA levels were 56% and 73%, respectively, in two individuals with FTLD with TAR DNAbinding protein 43-positive inclusions (Bit-Ivan EN et al. J. Neuropathol. Exp. Neurol., 2014 May;73:467-73). In one family, this variant segregated with dementia in 3 affected individuals (Galimberti D et al. Mov. Disord., 2017 03;32:476-478). These nucleotide positions are well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 7 of the GRN gene. It does not directly change the encoded amino acid sequence of the GRN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs778599933, gnomAD 0.002%). This variant has been observed in individuals with autosomal dominant frontotemporal lobar degeneration (PMID: 20975516, 24709683, 27632209, 27859661). This variant is also known as IVS6+5_8delGTGA (g.101707_101710delGTGA) and g.1642_1645delTGAG (IVS7 + 1delTGAG). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20975516). For these reasons, this variant has been classified as Pathogenic. -

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

Mar 01, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in GRN is an intronic variant located in intron 7. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.004% (40/1,104,774 alleles) in the European (non-Finnish) population. The prevalence of the variant in individuals with frontotemporal dementia (FTD) is significantly increased compared with the prevalence in controls (PMID: 20975516, 24709683, 27632209, 27859661, 30475763, 31914217, 36264717, 33141172; gnomAD v4.0). The variant has been reported to segregate with FTD in multiple families (PMID: 27859661, 24709683, 30475763). The results from an in silico splicing predictor (SpliceAI) indicate that this variant may impact splicing by disrupting the donor splice site of intron 7 of GRN. This prediction is confirmed by RNA studies in patient cells (PMID: 20975516). Furthermore, progranulin levels in the serum/brain were significantly reduced in individuals with the variant (PMID: 20975516, 24709683, 27859661, 30475763). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4, PVS1. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -44
DS_DL_spliceai		0.40		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs778599933; hg19: chr17-42428168;