chr10-13278327-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006214.4(PHYH):ā€‹c.991G>Cā€‹(p.Val331Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000125 in 1,612,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 32)
Exomes š‘“: 0.00013 ( 0 hom. )

Consequence

PHYH
NM_006214.4 missense

Scores

3
13
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.04
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PHYHNM_006214.4 linkuse as main transcriptc.991G>C p.Val331Leu missense_variant 9/9 ENST00000263038.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PHYHENST00000263038.9 linkuse as main transcriptc.991G>C p.Val331Leu missense_variant 9/91 NM_006214.4 P1O14832-1
PHYHENST00000396920.7 linkuse as main transcriptc.940G>C p.Val314Leu missense_variant 9/95
PHYHENST00000396913.6 linkuse as main transcriptc.691G>C p.Val231Leu missense_variant 8/85 O14832-2

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251376
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000133
AC:
194
AN:
1460722
Hom.:
0
Cov.:
29
AF XY:
0.000135
AC XY:
98
AN XY:
726806
show subpopulations
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:
0.000163
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000109
Hom.:
0
Bravo
AF:
0.0000642
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 09, 2021The c.991G>C (p.V331L) alteration is located in exon 9 (coding exon 9) of the PHYH gene. This alteration results from a G to C substitution at nucleotide position 991, causing the valine (V) at amino acid position 331 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 04, 2022This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 331 of the PHYH protein (p.Val331Leu). This variant is present in population databases (rs200245065, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PHYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 837093). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
.;D;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Benign
0.062
D
MetaRNN
Uncertain
0.60
D;D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Pathogenic
3.2
.;M;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-2.4
N;N;N
REVEL
Uncertain
0.64
Sift
Uncertain
0.0050
D;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
0.98, 0.89
.;D;P
Vest4
0.41
MutPred
0.36
.;Loss of methylation at K332 (P = 0.0352);.;
MVP
0.88
MPC
0.49
ClinPred
0.66
D
GERP RS
5.7
Varity_R
0.48
gMVP
0.74

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200245065; hg19: chr10-13320327; API