rs764211125

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001365677.2(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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q140R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

P4HA2
NM_001365677.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.24

Publications

3 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: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

P4HA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-132213966-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 372166.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA2	NM_001365677.2 link	c.419A>T	p.Gln140Leu	missense_variant	Exon 5 of 15	ENST00000379104.7	NP_001352606.1
P4HA2	NM_001017974.2 link	c.419A>T	p.Gln140Leu	missense_variant	Exon 5 of 15	ENST00000360568.8	NP_001017974.1	O15460-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA2	ENST00000379104.7 link	c.419A>T	p.Gln140Leu	missense_variant	Exon 5 of 15	1	NM_001365677.2	ENSP00000368398.2		O15460-1
P4HA2	ENST00000360568.8 link	c.419A>T	p.Gln140Leu	missense_variant	Exon 5 of 15	1	NM_001017974.2	ENSP00000353772.3		O15460-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251448

AF XY:

0.0000147

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111944

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000261

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

(source)

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;.;.;.;.;.;.

PhyloP100

6.2

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

Mutation Taster

=44/56

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over