rs566116760

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS2

The NM_006214.4(PHYH):c.1010_1012dupATC(p.Asn337_Leu338insHis) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00213 in 1,609,052 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L338L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

PHYH
NM_006214.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:2

Conservation

PhyloP100: 4.23

Publications

4 publications found

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 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

PHYH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_006214.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 10-13278305-A-AGAT is Benign according to our data. Variant chr10-13278305-A-AGAT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 444210.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYH	NM_006214.4 link	c.1010_1012dupATC	p.Asn337_Leu338insHis	conservative_inframe_insertion	Exon 9 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.1010_1012dupATC	p.Asn337_Leu338insHis	conservative_inframe_insertion	Exon 9 of 9	1	NM_006214.4	ENSP00000263038.4	O14832-1
PHYH	ENST00000396920.7 link	c.959_961dupATC	p.Asn320_Leu321insHis	conservative_inframe_insertion	Exon 9 of 9	5		ENSP00000380126.3	B1ALH6
PHYH	ENST00000396913.6 link	c.710_712dupATC	p.Asn237_Leu238insHis	conservative_inframe_insertion	Exon 8 of 8	5		ENSP00000380121.2	O14832-2

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00204

AC:

513

AN:

251408

AF XY:

0.00205

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00295

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00218

AC:

3182

AN:

1456730

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1513

AN XY:

725128

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33384

American (AMR)

AF:

0.00201

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.000162

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00283

AC:

151

AN:

53396

Middle Eastern (MID)

AF:

0.000870

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00247

AC:

2736

AN:

1107380

Other (OTH)

AF:

0.00226

AC:

136

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

144

287

431

574

718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00160

AC:

243

AN:

152322

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41576

American (AMR)

AF:

0.00216

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00219

AC:

149

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.00187

EpiCase

AF:

0.00196

EpiControl

AF:

0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PHYH: BS2 -

Jan 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

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:no assertion criteria provided

Collection Method:research

- -

not specified

Uncertain:1

Mar 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PHYH c.1010_1012dupATC (p.Asn337_Leu338insHis) results in an in-frame insertion that is predicted to insert 1 amino acid into the encoded protein. The variant allele was found at a frequency of 0.002 in 251408 control chromosomes in the gnomAD database, including 1 homozygote. c.1010_1012dupATC has been reported in the literature in individuals affected with retinal disease or nonsyndromic cleft lip and palate without strong evidence of causality (Watson_2014, Aylward_2016, Dieriro_2020). These reports do not provide unequivocal conclusions about association of the variant with Phytanic Acid Storage Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25133751, 27229527, 32483926). ClinVar contains an entry for this variant (Variation ID: 444210). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Optic atrophy

Uncertain:1

Jan 01, 2023

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Mutation Taster

=58/42

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over