rs1747682

Positions:

• chr10-13295588-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006214.4(PHYH):​c.153C>T​(p.Asn51=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 1,313,394 control chromosomes in the GnomAD database, including 648,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71952 hom., cov: 31)
  • Exomes 𝑓: 1.0 (576610 hom.)
• Consequence: PHYH NM_006214.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.222

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-13295588-G-A is Benign according to our data. Variant chr10-13295588-G-A is described in ClinVar as [Benign]. Clinvar id is 129891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13295588-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.222 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHYH	NM_006214.4	c.153C>T	p.Asn51=	synonymous_variant	3/9	ENST00000263038.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHYH	ENST00000263038.9	c.153C>T	p.Asn51=	synonymous_variant	3/9	1	NM_006214.4	P1

Frequencies

GnomAD3 genomes AF: 0.971 AC: 147752 AN: 152128 Hom.: 71907 Cov.: 31

Gnomad AFR AF: 0.900

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.977

GnomAD3 exomes AF: 0.992 AC: 249233 AN: 251144 Hom.: 123749 AF XY: 0.994 AC XY: 135046 AN XY: 135798

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1156972 AN: 1161148 Hom.: 576610 Cov.: 17 AF XY: 0.997 AC XY: 590830 AN XY: 592650

Gnomad4 AFR exome AF: 0.888

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 0.996

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.992

GnomAD4 genome AF: 0.971 AC: 147856 AN: 152246 Hom.: 71952 Cov.: 31 AF XY: 0.972 AC XY: 72357 AN XY: 74440

Gnomad4 AFR AF: 0.900

Gnomad4 AMR AF: 0.991

Gnomad4 ASJ AF: 0.995

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.977

Alfa AF: 0.995 Hom.: 75698

Bravo AF: 0.967

Asia WGS AF: 0.996 AC: 3464 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -

Phytanic acid storage disease Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.8
DANN	Benign	0.61

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

Other links and lift over

dbSNP: rs1747682; hg19: chr10-13337588;