Variant rs764211125 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001017974.2(P4HA2):c.419A>T(p.Gln140Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

P4HA2
NM_001017974.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.24

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P4HA2	NM_001365677.2 linkuse as main transcript	c.419A>T	p.Gln140Leu	missense_variant	5/15	ENST00000379104.7	NP_001352606.1
P4HA2	NM_001017974.2 linkuse as main transcript	c.419A>T	p.Gln140Leu	missense_variant	5/15	ENST00000360568.8	NP_001017974.1	O15460-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P4HA2	ENST00000379104.7 linkuse as main transcript	c.419A>T	p.Gln140Leu	missense_variant	5/15	1	NM_001365677.2	ENSP00000368398.2		O15460-1
P4HA2	ENST00000360568.8 linkuse as main transcript	c.419A>T	p.Gln140Leu	missense_variant	5/15	1	NM_001017974.2	ENSP00000353772.3		O15460-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251448

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135890

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000422

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;D;.;.;D;D;.;D;.;.;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;.;.;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.7

D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.012

D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.029

D;D;D;D;D;D;.;T;T;.;.;.

Polyphen

0.76

P;P;P;P;P;P;.;.;.;.;.;.

Vest4

0.80

MutPred

0.86

Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);.;Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);Loss of phosphorylation at Y143 (P = 0.1481);

MVP

0.88

MPC

0.85

ClinPred

0.95

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.93

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over