10-13283750-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006214.4(PHYH):​c.766_767del​(p.Val256PhefsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Consequence

PHYH
NM_006214.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.21
Variant links:
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-13283750-AAC-A is Pathogenic according to our data. Variant chr10-13283750-AAC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208603.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PHYHNM_006214.4 linkuse as main transcriptc.766_767del p.Val256PhefsTer14 frameshift_variant 7/9 ENST00000263038.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PHYHENST00000263038.9 linkuse as main transcriptc.766_767del p.Val256PhefsTer14 frameshift_variant 7/91 NM_006214.4 P1O14832-1
PHYHENST00000396913.6 linkuse as main transcriptc.466_467del p.Val156PhefsTer14 frameshift_variant 6/85 O14832-2
PHYHENST00000396920.7 linkuse as main transcriptc.715_716del p.Val239PhefsTer14 frameshift_variant 7/95
PHYHENST00000453759.6 linkuse as main transcriptc.466_467del p.Val156PhefsTer14 frameshift_variant 7/75

Frequencies

GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Phytanic acid storage disease Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 12, 2014The Val256PhefsX14 variant in PHYH has not been previously identified in the literature or in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 256 and lead to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of PHYH function is a known disease mechanism in Refsum disease. In summary, although additional studies are required to fully establish its clinical significance, the Val256PhefsX14 variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs797045100; hg19: chr10-13325750; API