10-13288402-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006214.4(PHYH):c.636A>G(p.Thr212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,770 control chromosomes in the GnomAD database, including 53,733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6431 hom., cov: 32)
  • Exomes 𝑓: 0.25 (47302 hom.)
• Consequence: PHYH NM_006214.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 10-13288402-T-C is Benign according to our data. Variant chr10-13288402-T-C is described in ClinVar as [Benign]. Clinvar id is 95349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-13288402-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHYH	NM_006214.4	c.636A>G	p.Thr212=	synonymous_variant	6/9	ENST00000263038.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHYH	ENST00000263038.9	c.636A>G	p.Thr212=	synonymous_variant	6/9	1	NM_006214.4	P1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42556 AN: 152004 Hom.: 6413 Cov.: 32

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.233 AC: 58616 AN: 251216 Hom.: 7676 AF XY: 0.228 AC XY: 30986 AN XY: 135842

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.0891

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.249 AC: 364641 AN: 1461648 Hom.: 47302 Cov.: 38 AF XY: 0.246 AC XY: 179092 AN XY: 727116

Gnomad4 AFR exome AF: 0.401

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.226

Gnomad4 EAS exome AF: 0.146

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.280

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.280 AC: 42622 AN: 152122 Hom.: 6431 Cov.: 32 AF XY: 0.277 AC XY: 20631 AN XY: 74376

Gnomad4 AFR AF: 0.393

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.276

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.235

Alfa AF: 0.252 Hom.: 9587

Bravo AF: 0.278

Asia WGS AF: 0.165 AC: 571 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.236

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2013	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Phytanic acid storage disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	1.3
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs473407; hg19: chr10-13330402; COSMIC: COSV53816118; COSMIC: COSV53816118;