rs397514468
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3PP5_Moderate
The NM_001104631.2(PDE4D):c.682C>G(p.Gln228Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q228P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001104631.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDE4D | NM_001104631.2 | c.682C>G | p.Gln228Glu | missense_variant, splice_region_variant | 3/15 | ENST00000340635.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDE4D | ENST00000340635.11 | c.682C>G | p.Gln228Glu | missense_variant, splice_region_variant | 3/15 | 1 | NM_001104631.2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2022 | ClinVar contains an entry for this variant (Variation ID: 30039). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PDE4D function (PMID: 24203977). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with acrodysostosis (PMID: 22464252). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 228 of the PDE4D protein (p.Gln228Glu). - |
Acrodysostosis 2 with or without hormone resistance Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 28, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at