rs201578674
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_006214.4(PHYH):c.135-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,108,744 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00017 ( 2 hom. )
Consequence
PHYH
NM_006214.4 splice_acceptor
NM_006214.4 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.61
Genes affected
PHYH (HGNC:8940): (phytanoyl-CoA 2-hydroxylase) This gene is a member of the PhyH family and encodes a peroxisomal protein that is involved in the alpha-oxidation of 3-methyl branched fatty acids. Specifically, this protein converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Mutations in this gene have been associated with Refsum disease (RD) and deficient protein activity has been associated with Zellweger syndrome and rhizomelic chondrodysplasia punctata. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.108161256 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3, offset of 37, new splice context is: acgttctaaccctggaacAGaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP5
Variant 10-13295608-T-C is Pathogenic according to our data. Variant chr10-13295608-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PHYH | NM_006214.4 | c.135-2A>G | splice_acceptor_variant | ENST00000263038.9 | NP_006205.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PHYH | ENST00000263038.9 | c.135-2A>G | splice_acceptor_variant | 1 | NM_006214.4 | ENSP00000263038 | P1 |
Frequencies
GnomAD3 genomes 0.000177 AC: 27AN: 152114Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000998 AC: 25AN: 250504Hom.: 0 AF XY: 0.0000959 AC XY: 13AN XY: 135534
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GnomAD4 exome AF: 0.000167 AC: 160AN: 956630Hom.: 2 Cov.: 13 AF XY: 0.000153 AC XY: 76AN XY: 498288
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GnomAD4 genome 0.000177 AC: 27AN: 152114Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10AN XY: 74320
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Phytanic acid storage disease Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 29, 2018 | The PHYH c.135-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.135-2A>G variant is described in four studies in which it has been detected in a total of ten individuals with Refsum disease, seven of whom carried the variant in a homozygous state and three in a compound heterozygous state (Mihalik et al. 1997; Jansen et al. 1997; Jansen et al. 2000; Finsterer et al. 2008). Mihalik et al. (1997) and Jansen et al., (1997) both identified the c.135-2A>G variant in a homozygous state in an individual with Refsum disease and found expression of a truncated mRNA due to exon skipping. The c.135-2A>G variant was found to alter the consensus splice acceptor site (Mihalik et al. 1997). Jansen et al. (2000) subsequently detected the c.135-2A>G variant in an additional six patients, all of whom had deficient PHYH activity in fibroblasts. Control information is unavailable for the c.135-2A>G variant which is reported at a frequency of 0.000245 in the European (non-Finnish) population of the Genome Aggregation Database. Heterologous expression in yeast demonstrated no detectable PHYH enzyme activity (Jansen et al. 2000). Immunoblotting experiments revealed a shorter protein and a reduction in protein expression compared to wild type suggesting that the c.135-2A>G variant protein is less stable and degrades more rapidly (Jansen et al. 2000). Based on the collective evidence, the c.135-2A>G variant is classified as pathogenic for Refsum disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 28, 2024 | Variant summary: PHYH c.135-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. The variant allele was found at a frequency of 0.0001 in 250504 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PHYH causing Phytanic Acid Storage Disease, allowing no conclusion about variant significance. c.135-2A>G has been reported in the literature in multiple individuals affected with Phytanic Acid Storage Disease (e.g. Dubot_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31240149). ClinVar contains an entry for this variant (Variation ID: 7581). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change affects an acceptor splice site in intron 2 of the PHYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs201578674, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with clinical features of Refsum disease (PMID: 9326939, 17905308, 31240149). ClinVar contains an entry for this variant (Variation ID: 7581). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 9326939). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 08, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2023 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 14974078, 25525159, 28470644, 9326939, 10767344, 18612766, 17905308, 31240149, 34426522, 32773395, 31816670) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 19, 2021 | PVS1, PS3, PS4_moderate, PM2, PM3, PP1 - |
Refsum disease, adult, 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2000 | - - |
PHYH-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 2024 | The PHYH c.135-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous state in two unrelated patients with Refsum disease, and functional studies demonstrated this variant leads to exon skipping (Mihalik. 1997. PubMed ID: 9326939; Dubot. 2019. PubMed ID: 31240149). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in PHYH are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Retinitis pigmentosa Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The c.135-2A>G variant in PHYH was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D
GERP RS
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_AL_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at