NM_006214.4:c.734G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006214.4(PHYH):c.734G>A(p.Arg245Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00727 in 1,613,820 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0069 ( 12 hom., cov: 31)

Exomes 𝑓: 0.0073 ( 70 hom. )

Consequence

PHYH
NM_006214.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:9

Conservation

PhyloP100: 3.39

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0109907985).

BP6

Variant 10-13283784-C-T is Benign according to our data. Variant chr10-13283784-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198539.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Likely_pathogenic=1, Benign=7, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00695 (1057/152118) while in subpopulation SAS AF= 0.0125 (60/4814). AF 95% confidence interval is 0.00994. There are 12 homozygotes in gnomad4. There are 588 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYH	NM_006214.4 link	c.734G>A	p.Arg245Gln	missense_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.734G>A	p.Arg245Gln	missense_variant	Exon 7 of 9	1	NM_006214.4	ENSP00000263038.4	O14832-1
PHYH	ENST00000396920.7 link	c.683G>A	p.Arg228Gln	missense_variant	Exon 7 of 9	5		ENSP00000380126.3	B1ALH6
PHYH	ENST00000396913.6 link	c.434G>A	p.Arg145Gln	missense_variant	Exon 6 of 8	5		ENSP00000380121.2	O14832-2
PHYH	ENST00000453759.6 link	c.434G>A	p.Arg145Gln	missense_variant	Exon 7 of 7	5		ENSP00000412525.2	C9IYS5

Frequencies

GnomAD3 genomes

AF:

0.00696

AC:

1058

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0129

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00829

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00761

AC:

1914

AN:

251492

Hom.:

AF XY:

0.00834

AC XY:

1134

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0127

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.00741

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00730

AC:

10671

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

5547

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00199

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.0242

Gnomad4 NFE exome

AF:

0.00684

Gnomad4 OTH exome

AF:

0.00672

GnomAD4 genome

AF:

0.00695

AC:

1057

AN:

152118

Hom.:

Cov.:

AF XY:

0.00791

AC XY:

588

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0125

Gnomad4 FIN

AF:

0.0299

Gnomad4 NFE

AF:

0.00829

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00686

Hom.:

Bravo

AF:

0.00404

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00784

AC:

952

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.00913

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Phytanic acid storage disease

Uncertain:1Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

South Asian population allele frequency is 1.166% (rs62619919, 389/30616 alleles, 6 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Sep 01, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHYH: BP4, BS1 -

Aug 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14974078, 10767344, 27229527, 27535533) -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Nov 08, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic cleft lip palate

Pathogenic:1

Mar 27, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vitamin D-dependent rickets type II with alopecia

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The p.Arg245Gln variant in PHYH has been identified in cis with p.Asp177Gly and in 4 individuals with Refsum disease, including 2 homozygotes and 2 heterozygotes (PMID: 10767344), and has been identified in >2% of European (Finnish) chromosomes and 9 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg245Gln variant may not impact protein function (PMID: 10767344). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive Refsum disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;D;.;.

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

T;D;D;T

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.1

.;M;.;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.2

D;D;D;D

REVEL

Pathogenic

0.71

Sift

Benign

0.061

T;D;D;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.95, 0.53

.;P;P;.

Vest4

0.75

MVP

0.82

MPC

0.42

ClinPred

0.059

GERP RS

4.8

Varity_R

0.77

gMVP

0.75

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over