17-44351461-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PP3_Strong
The NM_002087.4(GRN):c.933+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000059 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
GRN
NM_002087.4 splice_donor
NM_002087.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 8.81
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.1, offset of 17, new splice context is: cggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRN | NM_002087.4 | c.933+1G>T | splice_donor_variant | ENST00000053867.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRN | ENST00000053867.8 | c.933+1G>T | splice_donor_variant | 1 | NM_002087.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 149120Hom.: 0 Cov.: 33 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000585 AC: 8AN: 1366586Hom.: 0 Cov.: 35 AF XY: 0.00000586 AC XY: 4AN XY: 682080
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 149230Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 72894
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ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at