5-132198235-C-T

Variant summary

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

The NM_001365677.2(P4HA2):​c.1342G>A​(p.Gly448Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 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: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

P4HA2
NM_001365677.2 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
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]

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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, 0.952

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
P4HA2NM_001365677.2 linkuse as main transcriptc.1342G>A p.Gly448Arg missense_variant 12/15 ENST00000379104.7
P4HA2NM_001017974.2 linkuse as main transcriptc.1365+86G>A intron_variant ENST00000360568.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
P4HA2ENST00000379104.7 linkuse as main transcriptc.1342G>A p.Gly448Arg missense_variant 12/151 NM_001365677.2 P4O15460-1
P4HA2ENST00000360568.8 linkuse as main transcriptc.1365+86G>A intron_variant 1 NM_001017974.2 A1O15460-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
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.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 30, 2024The c.1342G>A (p.G448R) alteration is located in exon 12 (coding exon 11) of the P4HA2 gene. This alteration results from a G to A substitution at nucleotide position 1342, causing the glycine (G) at amino acid position 448 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.61
D;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;.;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Uncertain
0.11
D
MutationAssessor
Pathogenic
4.0
H;H;H
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-6.9
D;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.015
D;D;D
Sift4G
Uncertain
0.018
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.97
MutPred
0.82
Gain of methylation at G448 (P = 0.0263);Gain of methylation at G448 (P = 0.0263);Gain of methylation at G448 (P = 0.0263);
MVP
0.93
MPC
0.94
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.58
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.42
Position offset: 36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-131533928; API