rs797045100

Positions:

• chr10-13283750-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.21

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]

ACMG classification

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	Protein	UniProt
PHYH	NM_006214.4	c.766_767del	p.Val256PhefsTer14	frameshift_variant	7/9	ENST00000263038.9	NP_006205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHYH	ENST00000263038.9	c.766_767del	p.Val256PhefsTer14	frameshift_variant	7/9	1	NM_006214.4	ENSP00000263038	P1
PHYH	ENST00000396913.6	c.466_467del	p.Val156PhefsTer14	frameshift_variant	6/8	5		ENSP00000380121
PHYH	ENST00000396920.7	c.715_716del	p.Val239PhefsTer14	frameshift_variant	7/9	5		ENSP00000380126
PHYH	ENST00000453759.6	c.466_467del	p.Val156PhefsTer14	frameshift_variant	7/7	5		ENSP00000412525

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

Submissions by phenotype

Phytanic acid storage disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 12, 2014

The 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

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

Other links and lift over

dbSNP: rs797045100; hg19: chr10-13325750;