rs201499815

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_001323082.2(PHYH):c.684+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000977 in 1,613,450 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 5 hom. )

Consequence

PHYH
NM_001323082.2 splice_region, intron

Scores

Splicing: ADA: 0.9985

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7B:2

Conservation

PhyloP100: 2.23

Publications

2 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.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00101 (1480/1461116) while in subpopulation SAS AF = 0.0045 (388/86220). AF 95% confidence interval is 0.00413. There are 5 homozygotes in GnomAdExome4. There are 821 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323082.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PHYH	NM_006214.4	MANE Select	c.678+5G>T	splice_region intron	N/A	NP_006205.1
PHYH	NM_001323082.2		c.684+5G>T	splice_region intron	N/A	NP_001310011.1
PHYH	NM_001323083.2		c.415-4516G>T	intron	N/A	NP_001310012.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PHYH	ENST00000263038.9	TSL:1 MANE Select	c.678+5G>T	splice_region intron	N/A	ENSP00000263038.4
PHYH	ENST00000858006.1		c.678+5G>T	splice_region intron	N/A	ENSP00000528065.1
PHYH	ENST00000943581.1		c.642+5G>T	splice_region intron	N/A	ENSP00000613640.1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00122

AC:

307

AN:

251112

AF XY:

0.00143

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00477

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.000775

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00101

AC:

1480

AN:

1461116

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

821

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

113

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00450

AC:

388

AN:

86220

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00343

AC:

AN:

5254

European-Non Finnish (NFE)

AF:

0.000755

AC:

840

AN:

1111884

Other (OTH)

AF:

0.00144

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

151

227

302

378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.000630

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00498

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

68028

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000687

Hom.:

Bravo

AF:

0.000510

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00125

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Phytanic acid storage disease (2)

Retinal dystrophy (2)

PHYH-related disorder (1)

Phytanoyl-CoA hydroxylase deficiency (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

2.2

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.35

Position offset: 5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over