rs104894174
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_006214.4(PHYH):c.824G>A(p.Arg275Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006214.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHYH | NM_006214.4 | c.824G>A | p.Arg275Gln | missense_variant | 7/9 | ENST00000263038.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHYH | ENST00000263038.9 | c.824G>A | p.Arg275Gln | missense_variant | 7/9 | 1 | NM_006214.4 | P1 | |
PHYH | ENST00000396920.7 | c.773G>A | p.Arg258Gln | missense_variant | 7/9 | 5 | |||
PHYH | ENST00000396913.6 | c.524G>A | p.Arg175Gln | missense_variant | 6/8 | 5 | |||
PHYH | ENST00000453759.6 | c.524G>A | p.Arg175Gln | missense_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152066Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251480Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135914
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727230
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152066Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74276
ClinVar
Submissions by phenotype
Phytanic acid storage disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Refsum disease, adult, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2000 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 275 of the PHYH protein (p.Arg275Gln). This variant is present in population databases (rs104894174, gnomAD 0.02%). This missense change has been observed in individuals with Refsum disease (PMID: 10767344). ClinVar contains an entry for this variant (Variation ID: 7588). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHYH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PHYH function (PMID: 10767344, 11555634). This variant disrupts the p.Arg275 amino acid residue in PHYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9657395, 10767344, 28041643). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at