10-13298236-G-T

Variant names:

• chr10-13298236-G-T
• rs28938169
• NM_006214.4:c.85C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001323082.2(PHYH):​c.85C>A​(p.Pro29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P29S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PHYH NM_001323082.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• adult Refsum disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Orphanet
• phytanoyl-CoA hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323082.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYH	NM_006214.4	MANE Select	c.85C>A	p.Pro29Thr	missense	Exon 2 of 9	NP_006205.1
	PHYH	NM_001323082.2		c.85C>A	p.Pro29Thr	missense	Exon 2 of 9	NP_001310011.1
	PHYH	NM_001323083.2		c.85C>A	p.Pro29Thr	missense	Exon 2 of 7	NP_001310012.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYH	ENST00000263038.9	TSL:1 MANE Select	c.85C>A	p.Pro29Thr	missense	Exon 2 of 9	ENSP00000263038.4
	PHYH	ENST00000858006.1		c.85C>A	p.Pro29Thr	missense	Exon 2 of 9	ENSP00000528065.1
	PHYH	ENST00000943581.1		c.85C>A	p.Pro29Thr	missense	Exon 2 of 9	ENSP00000613640.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.4
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.47
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.73	P
Vest4		0.24
MutPred		0.63		Gain of catalytic residue at P29 (P = 0.0071)
MVP		0.90
MPC		0.32
ClinPred		0.93	D
GERP RS		3.3
Varity_R		0.062
gMVP		0.52
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs28938169; hg19: chr10-13340236;