rs28938169

Positions:

• chr10-13298236-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006214.4(PHYH):​c.85C>T​(p.Pro29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,593,910 control chromosomes in the GnomAD database, including 23,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P29P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1806 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21932 hom.)
• Consequence: PHYH NM_006214.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.37

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017195046).
• BP6: Variant 10-13298236-G-A is Benign according to our data. Variant chr10-13298236-G-A is described in ClinVar as [Benign]. Clinvar id is 7582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13298236-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHYH	NM_006214.4	c.85C>T	p.Pro29Ser	missense_variant	2/9	ENST00000263038.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHYH	ENST00000263038.9	c.85C>T	p.Pro29Ser	missense_variant	2/9	1	NM_006214.4	P1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22292 AN: 152020 Hom.: 1803 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0923

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.148 AC: 37080 AN: 251292 Hom.: 3229 AF XY: 0.148 AC XY: 20038 AN XY: 135838

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.0147

Gnomad SAS exome AF: 0.0998

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.167 AC: 241357 AN: 1441772 Hom.: 21932 Cov.: 26 AF XY: 0.166 AC XY: 119198 AN XY: 718518

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.0147

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.147 AC: 22322 AN: 152138 Hom.: 1806 Cov.: 31 AF XY: 0.146 AC XY: 10856 AN XY: 74356

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0932

Gnomad4 FIN AF: 0.220

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.133

Alfa AF: 0.165 Hom.: 3442

Bravo AF: 0.137

TwinsUK AF: 0.194 AC: 721

ALSPAC AF: 0.172 AC: 664

ESP6500AA AF: 0.122 AC: 539

ESP6500EA AF: 0.177 AC: 1524

ExAC AF: 0.149 AC: 18138

Asia WGS AF: 0.0740 AC: 257 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.168

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Phytanic acid storage disease Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Refsum disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:4

Benign, no assertion criteria provided	literature only	OMIM	May 01, 2000	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2018	This variant is associated with the following publications: (PMID: 10767344, 25525159, 20220177, 20981092, 11555634) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.054	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.25	T;T;.
Polyphen		0.047	B;B;.
Vest4		0.12
MPC		0.15
ClinPred		0.012	T
GERP RS		3.3
Varity_R		0.048
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs28938169; hg19: chr10-13340236; COSMIC: COSV53815382; COSMIC: COSV53815382;