10-13278332-C-G

Variant names:

• chr10-13278332-C-G
• rs144085594
• NM_006214.4:c.986G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006214.4(PHYH):​c.986G>C​(p.Arg329Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PHYH NM_006214.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHYH	NM_006214.4	c.986G>C	p.Arg329Pro	missense_variant	Exon 9 of 9	ENST00000263038.9	NP_006205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHYH	ENST00000263038.9	c.986G>C	p.Arg329Pro	missense_variant	Exon 9 of 9	1	NM_006214.4	ENSP00000263038.4
PHYH	ENST00000396920.7	c.935G>C	p.Arg312Pro	missense_variant	Exon 9 of 9	5		ENSP00000380126.3
PHYH	ENST00000396913.6	c.686G>C	p.Arg229Pro	missense_variant	Exon 8 of 8	5		ENSP00000380121.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460336 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726612

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with PHYH-related conditions. This sequence change replaces arginine with proline at codon 329 of the PHYH protein (p.Arg329Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	.;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	-0.0090
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.1	.;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.74
MutPred		0.58		.;Loss of MoRF binding (P = 3e-04);.;
MVP		0.87
MPC		0.76
ClinPred		0.99	D
GERP RS		1.8
Varity_R		0.96
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144085594; hg19: chr10-13320332;