rs62619919
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.0069 ( 12 hom., cov: 31)
Exomes 𝑓: 0.0073 ( 70 hom. )
Consequence
PHYH
NM_006214.4 missense
NM_006214.4 missense
Scores
3
6
9
Clinical Significance
Conservation
PhyloP100: 3.39
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 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 [Likely_benign]. Clinvar id is 198539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PHYH | NM_006214.4 | c.734G>A | p.Arg245Gln | missense_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.734G>A | p.Arg245Gln | missense_variant | 7/9 | 1 | NM_006214.4 | ENSP00000263038 | P1 | |
PHYH | ENST00000396920.7 | c.683G>A | p.Arg228Gln | missense_variant | 7/9 | 5 | ENSP00000380126 | |||
PHYH | ENST00000396913.6 | c.434G>A | p.Arg145Gln | missense_variant | 6/8 | 5 | ENSP00000380121 | |||
PHYH | ENST00000453759.6 | c.434G>A | p.Arg145Gln | missense_variant | 7/7 | 5 | ENSP00000412525 |
Frequencies
GnomAD3 genomes AF: 0.00696 AC: 1058AN: 152000Hom.: 12 Cov.: 31
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GnomAD3 exomes AF: 0.00761 AC: 1914AN: 251492Hom.: 19 AF XY: 0.00834 AC XY: 1134AN XY: 135922
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GnomAD4 exome AF: 0.00730 AC: 10671AN: 1461702Hom.: 70 Cov.: 32 AF XY: 0.00763 AC XY: 5547AN XY: 727176
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GnomAD4 genome AF: 0.00695 AC: 1057AN: 152118Hom.: 12 Cov.: 31 AF XY: 0.00791 AC XY: 588AN XY: 74348
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ESP6500AA
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Uncertain:1Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Phytanic acid storage disease Uncertain:1Benign:3
Uncertain significance, flagged submission | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Mar 06, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | May 04, 2023 | 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 - |
Benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Sep 01, 2024 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | PHYH: BP4, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 06, 2020 | This variant is associated with the following publications: (PMID: 14974078, 10767344, 27229527, 27535533) - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 08, 2014 | - - |
Nonsyndromic cleft lip palate Pathogenic:1
Likely pathogenic, flagged submission | research | University of Washington Center for Mendelian Genomics, University of Washington | Mar 27, 2016 | - - |
Vitamin D-dependent rickets type II with alopecia Benign:1
Benign, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;D;T
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;D;D;T
Sift4G
Benign
T;T;T;T
Polyphen
0.95, 0.53
.;P;P;.
Vest4
MVP
MPC
0.42
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at