rs606231221

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_002087.4(GRN):c.835+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GRN
NM_002087.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.41

Publications

0 publications found

Variant links:

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

GRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-44351164-G-A is Pathogenic according to our data. Variant chr17-44351164-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16012.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 link	c.835+1G>A		splice_donor_variant, intron_variant	Intron 8 of 12	ENST00000053867.8	NP_002078.1	P28799-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRN	ENST00000053867.8 link	c.835+1G>A		splice_donor_variant, intron_variant	Intron 8 of 12	1	NM_002087.4	ENSP00000053867.2		P28799-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251312

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000244

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Sep 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 16012). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 16862116). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is also known as IVS8+1G>A. This sequence change affects a donor splice site in intron 8 of the GRN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs606231221, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with frontotemporal dementia (PMID: 16862116). -

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Pathogenic:1

Aug 24, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.77

PhyloP100

4.4

GERP RS

4.8

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over