Genetic Variant P4HA2:p.Val394Ile (chr5-132203819-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001017974.2(P4HA2):c.1180G>A(p.Val394Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

P4HA2
NM_001017974.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.50

Publications

0 publications found

Variant links:

Genes affected

P4HA2 (HGNC:8547): (prolyl 4-hydroxylase subunit alpha 2) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

P4HA2 Gene-Disease associations (from GenCC):

myopia
Inheritance: AD Classification: STRONG Submitted by: G2P
myopia 25, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

P4HA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20301217).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017974.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P4HA2	NM_001365677.2	MANE Plus Clinical	c.1180G>A	p.Val394Ile	missense	Exon 10 of 15	NP_001352606.1	O15460-1
P4HA2	NM_001017974.2	MANE Select	c.1180G>A	p.Val394Ile	missense	Exon 10 of 15	NP_001017974.1	O15460-2
P4HA2	NM_001142599.2		c.1180G>A	p.Val394Ile	missense	Exon 11 of 16	NP_001136071.1	O15460-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
P4HA2	ENST00000379104.7	TSL:1 MANE Plus Clinical	c.1180G>A	p.Val394Ile	missense	Exon 10 of 15	ENSP00000368398.2	O15460-1
P4HA2	ENST00000360568.8	TSL:1 MANE Select	c.1180G>A	p.Val394Ile	missense	Exon 10 of 15	ENSP00000353772.3	O15460-2
P4HA2	ENST00000166534.8	TSL:1	c.1180G>A	p.Val394Ile	missense	Exon 11 of 16	ENSP00000166534.4	O15460-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.025

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0068

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

2.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.50

REVEL

Benign

0.041

Sift

Benign

0.083

Sift4G

Benign

0.16

Polyphen

0.034

Vest4

0.21

MutPred

0.39

Loss of helix (P = 0.1299)

MVP

0.42

MPC

0.21

ClinPred

0.56

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.077

gMVP

0.61

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over