chr10-53806811-A-AT
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_001384140.1(PCDH15):c.4990dupA(p.Met1664fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
PCDH15
NM_001384140.1 frameshift
NM_001384140.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.227
Genes affected
PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0446 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-53806811-A-AT is Pathogenic according to our data. Variant chr10-53806811-A-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587635.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PCDH15 | NM_001384140.1 | c.4990dupA | p.Met1664fs | frameshift_variant | 38/38 | ENST00000644397.2 | NP_001371069.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PCDH15 | ENST00000644397.2 | c.4990dupA | p.Met1664fs | frameshift_variant | 38/38 | NM_001384140.1 | ENSP00000495195.1 |
Frequencies
GnomAD3 genomes 0.0000461 AC: 7AN: 151926Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248658Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135122
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GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461632Hom.: 0 Cov.: 33 AF XY: 0.0000591 AC XY: 43AN XY: 727098
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GnomAD4 genome 0.0000461 AC: 7AN: 151926Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74190
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Usher syndrome type 1F Pathogenic:2Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 13, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Met1664fs variant in PCDH15 has not been previously reported in the literature in individuals with Usher syndrome type 1F but has been identified in 0.0009% (2/35372) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs766484375). 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#: 587635) and has been interpreted as likely pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1664 and leads to a premature termination codon 18 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, the clinical significance of the p.Met1664fs variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PVS1_moderate (Richards 2015). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at