rs758921360
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_033056.4(PCDH15):c.3983+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,636 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
Consequence
NM_033056.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_001384140.1 | c.3983+1G>T | splice_donor_variant | ENST00000644397.2 | |||
PCDH15 | NM_033056.4 | c.3983+1G>T | splice_donor_variant | ENST00000320301.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.3983+1G>T | splice_donor_variant | 1 | NM_033056.4 | ||||
PCDH15 | ENST00000644397.2 | c.3983+1G>T | splice_donor_variant | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251452Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135894
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461636Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727154
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Usher syndrome type 1F Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The c.3983+1G>T variant in PCDH15 has been reported in 3 individuals with Usher syndrome type 1F (PMID: 25575603, 28984810, Kamenarova 2020) and has been identified in 0.003% (3/113732) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758921360). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 370764) and has been interpreted as pathogenic or likely pathogenic by Invitae, Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen), and Counsyl. Of the 3 affected individuals, 1 of those was a homozygote, and 2 were compound heterozygotes that carried reported likely pathogenic variants in trans and with unknown phase, which increases the likelihood that the c.3983+1G>T variant is pathogenic (VariationID: 370113; PMID: 25575603, 28984810, Kamenarova 2020). This variant is located in the 3' splice region. Computational tools predict a splicing impact through intron retention, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 08, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 370764). This variant is also known as IVS30+1G>T and c.3998+1G>T. Disruption of this splice site has been observed in individual(s) with Usher syndrome and profound hearing loss (PMID: 25575603, 28984810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs758921360, gnomAD 0.003%). This sequence change affects a donor splice site in intron 29 of the PCDH15 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at