chr10-13295608-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_006214.4(PHYH):c.135-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,108,744 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

PHYH
NM_006214.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.61

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 was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.109144546 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3, offset of 37, new splice context is: acgttctaaccctggaacAGaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 10-13295608-T-C is Pathogenic according to our data. Variant chr10-13295608-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYH	NM_006214.4 link	c.135-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 8	ENST00000263038.9	NP_006205.1	O14832-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHYH	ENST00000263038.9 link	c.135-2A>G		splice_acceptor_variant, intron_variant	Intron 2 of 8	1	NM_006214.4	ENSP00000263038.4		O14832-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000998

AC:

AN:

250504

AF XY:

0.0000959

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000167

AC:

160

AN:

956630

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

498288

show subpopulations

Gnomad4 AFR exome

AF:

0.0000410

AC:

AN:

24370

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44082

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

23082

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

37478

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

76000

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52888

Gnomad4 NFE exome

AF:

0.000237

AC:

154

AN:

650572

Gnomad4 Remaining exome

AF:

0.000115

AC:

AN:

43662

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000177

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.000121

AC:

0.000120685

AN:

0.000120685

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000323

AC:

0.000323472

AN:

0.000323472

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000226

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phytanic acid storage disease

Pathogenic:4

Aug 29, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PHYH c.135-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.135-2A>G variant is described in four studies in which it has been detected in a total of ten individuals with Refsum disease, seven of whom carried the variant in a homozygous state and three in a compound heterozygous state (Mihalik et al. 1997; Jansen et al. 1997; Jansen et al. 2000; Finsterer et al. 2008). Mihalik et al. (1997) and Jansen et al., (1997) both identified the c.135-2A>G variant in a homozygous state in an individual with Refsum disease and found expression of a truncated mRNA due to exon skipping. The c.135-2A>G variant was found to alter the consensus splice acceptor site (Mihalik et al. 1997). Jansen et al. (2000) subsequently detected the c.135-2A>G variant in an additional six patients, all of whom had deficient PHYH activity in fibroblasts. Control information is unavailable for the c.135-2A>G variant which is reported at a frequency of 0.000245 in the European (non-Finnish) population of the Genome Aggregation Database. Heterologous expression in yeast demonstrated no detectable PHYH enzyme activity (Jansen et al. 2000). Immunoblotting experiments revealed a shorter protein and a reduction in protein expression compared to wild type suggesting that the c.135-2A>G variant protein is less stable and degrades more rapidly (Jansen et al. 2000). Based on the collective evidence, the c.135-2A>G variant is classified as pathogenic for Refsum disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PHYH c.135-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. The variant allele was found at a frequency of 0.0001 in 250504 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PHYH causing Phytanic Acid Storage Disease, allowing no conclusion about variant significance. c.135-2A>G has been reported in the literature in multiple individuals affected with Phytanic Acid Storage Disease (e.g. Dubot_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31240149). ClinVar contains an entry for this variant (Variation ID: 7581). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:4

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 2 of the PHYH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs201578674, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with clinical features of Refsum disease (PMID: 9326939, 17905308, 31240149). ClinVar contains an entry for this variant (Variation ID: 7581). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 9326939). For these reasons, this variant has been classified as Pathogenic. -

Jan 19, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS3, PS4_moderate, PM2, PM3, PP1 -

Aug 07, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 14974078, 25525159, 28470644, 9326939, 10767344, 18612766, 17905308, 31240149, 34426522, 32773395, 31816670) -

Feb 08, 2018

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PHYH-related disorder

Pathogenic:1

Feb 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PHYH c.135-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in the homozygous state in two unrelated patients with Refsum disease, and functional studies demonstrated this variant leads to exon skipping (Mihalik. 1997. PubMed ID: 9326939; Dubot. 2019. PubMed ID: 31240149). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in PHYH are expected to be pathogenic. This variant is interpreted as pathogenic. -

REFSUM DISEASE, ADULT, 1

Pathogenic:1

May 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinitis pigmentosa

Pathogenic:1

Apr 01, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The c.135-2A>G variant in PHYH was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.7

Mutation Taster

=3/97

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AL_spliceai

1.0

Position offset: -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