chr1-150324893-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PVS1_ModeratePP3_StrongBS2
The NM_004698.4(PRPF3):c.-48-2A>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00095 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0067 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
PRPF3
NM_004698.4 splice_acceptor
NM_004698.4 splice_acceptor
Scores
2
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 1.31
Genes affected
PRPF3 (HGNC:17348): (pre-mRNA processing factor 3) The removal of introns from nuclear pre-mRNAs occurs on complexes called spliceosomes, which are made up of 4 small nuclear ribonucleoprotein (snRNP) particles and an undefined number of transiently associated splicing factors. This gene product is one of several proteins that associate with U4 and U6 snRNPs. Mutations in this gene are associated with retinitis pigmentosa-18. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09356725 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of 6, new splice context is: tttttttttttttggtgtAGtat. Cryptic site results in inframe 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.
BS2
?
High AC in GnomAdExome at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRPF3 | NM_004698.4 | c.-48-2A>T | splice_acceptor_variant | ENST00000324862.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRPF3 | ENST00000324862.7 | c.-48-2A>T | splice_acceptor_variant | 1 | NM_004698.4 | P1 | |||
PRPF3 | ENST00000496202.5 | n.115-2A>T | splice_acceptor_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 24AN: 25380Hom.: 0 Cov.: 0 FAILED QC
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GnomAD3 exomes AF: 0.000103 AC: 14AN: 135700Hom.: 0 AF XY: 0.0000658 AC XY: 5AN XY: 76004
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00669 AC: 3309AN: 494490Hom.: 1 Cov.: 19 AF XY: 0.00630 AC XY: 1586AN XY: 251626
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.000945 AC: 24AN: 25394Hom.: 0 Cov.: 0 AF XY: 0.00110 AC XY: 14AN XY: 12682
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Retinitis pigmentosa 18 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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_AG_spliceai
Position offset: 8
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at