dbSNP rs797045100: PHYH:p.Val256PhefsTer14 (chr10-13283750-AAC-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

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

The NM_006214.4(PHYH):c.766_767delGT(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]

PHYH links:

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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 rank	MANE	Protein	UniProt
PHYH	NM_006214.4 link	c.766_767delGT	p.Val256PhefsTer14	frameshift_variant	Exon 7 of 9	ENST00000263038.9	NP_006205.1	O14832-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHYH	ENST00000263038.9 link	c.766_767delGT	p.Val256PhefsTer14	frameshift_variant	Exon 7 of 9	1	NM_006214.4	ENSP00000263038.4	O14832-1
PHYH	ENST00000396920.7 link	c.715_716delGT	p.Val239PhefsTer14	frameshift_variant	Exon 7 of 9	5		ENSP00000380126.3	B1ALH6
PHYH	ENST00000396913.6 link	c.466_467delGT	p.Val156PhefsTer14	frameshift_variant	Exon 6 of 8	5		ENSP00000380121.2	O14832-2
PHYH	ENST00000453759.6 link	c.466_467delGT	p.Val156PhefsTer14	frameshift_variant	Exon 7 of 7	5		ENSP00000412525.2	C9IYS5

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Phytanic acid storage disease

Pathogenic:1

Jun 12, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name

Calibrated prediction

Score

Prediction

Splicing