chr10-13283784-C-T

Variant names:

• chr10-13283784-C-T
• rs62619919
• NM_006214.4:c.734G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006214.4(PHYH):​c.734G>A​(p.Arg245Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00727 in 1,613,820 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R245W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (70 hom.)
• Consequence: PHYH NM_006214.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:10
• Conservation: PhyloP100: 3.39
• Publications: 18 publications found

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, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• phytanoyl-CoA hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0109907985).
• BP6: Variant 10-13283784-C-T is Benign according to our data. Variant chr10-13283784-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198539.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00695 (1057/152118) while in subpopulation SAS AF = 0.0125 (60/4814). AF 95% confidence interval is 0.00994. There are 12 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006214.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYH	NM_006214.4	MANE Select	c.734G>A	p.Arg245Gln	missense	Exon 7 of 9	NP_006205.1	O14832-1
	PHYH	NM_001323082.2		c.740G>A	p.Arg247Gln	missense	Exon 7 of 9	NP_001310011.1
	PHYH	NM_001323083.2		c.470G>A	p.Arg157Gln	missense	Exon 5 of 7	NP_001310012.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYH	ENST00000263038.9	TSL:1 MANE Select	c.734G>A	p.Arg245Gln	missense	Exon 7 of 9	ENSP00000263038.4	O14832-1
	PHYH	ENST00000858006.1		c.701G>A	p.Arg234Gln	missense	Exon 7 of 9	ENSP00000528065.1
	PHYH	ENST00000943581.1		c.698G>A	p.Arg233Gln	missense	Exon 7 of 9	ENSP00000613640.1

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1058 AN: 152000 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00829

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00761 AC: 1914 AN: 251492 AF XY: 0.00834

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.00741

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00730 AC: 10671 AN: 1461702 Hom.: 70 Cov.: 32 AF XY: 0.00763 AC XY: 5547 AN XY: 727176

African (AFR) AF: 0.00108 AC: 36 AN: 33474

American (AMR) AF: 0.00203 AC: 91 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0131 AC: 1131 AN: 86254

European-Finnish (FIN) AF: 0.0242 AC: 1291 AN: 53420

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.00684 AC: 7609 AN: 1111834

Other (OTH) AF: 0.00672 AC: 406 AN: 60392

GnomAD4 genome AF: 0.00695 AC: 1057 AN: 152118 Hom.: 12 Cov.: 31 AF XY: 0.00791 AC XY: 588 AN XY: 74348

African (AFR) AF: 0.00113 AC: 47 AN: 41526

American (AMR) AF: 0.00157 AC: 24 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4814

European-Finnish (FIN) AF: 0.0299 AC: 317 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00829 AC: 564 AN: 67996

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00670 Hom.: 6

Bravo AF: 0.00404

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00784 AC: 952

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00913

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Phytanic acid storage disease (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
1	-	-	Nonsyndromic cleft lip palate (1)
-	1	-	Retinal dystrophy (1)
-	-	1	Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.4
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.71
Sift	Benign	0.061	T
Sift4G	Benign	0.17	T
Polyphen		0.95	P
Vest4		0.75
MVP		0.82
MPC		0.42
ClinPred		0.059	T
GERP RS		4.8
Varity_R		0.77
gMVP		0.75
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs62619919; hg19: chr10-13325784; COSMIC: COSV99036280; COSMIC: COSV99036280;