Genetic Variant P4HA1:p.Ile351Met (chr10-73046949-G-C) – 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_001017962.3(P4HA1):c.1053C>G(p.Ile351Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I351I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

P4HA1
NM_001017962.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.190

Publications

1 publications found

Variant links:

Genes affected

P4HA1 (HGNC:8546): (prolyl 4-hydroxylase subunit alpha 1) 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]

P4HA1 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=0.14494097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA1	NM_001017962.3 link	c.1053C>G	p.Ile351Met	missense_variant	Exon 8 of 15	ENST00000394890.7	NP_001017962.1	P13674-1
P4HA1	NM_000917.4 link	c.1053C>G	p.Ile351Met	missense_variant	Exon 8 of 15		NP_000908.2	P13674-2Q5VSQ6
P4HA1	NM_001142595.2 link	c.1053C>G	p.Ile351Met	missense_variant	Exon 9 of 16		NP_001136067.1	P13674-1
P4HA1	NM_001142596.2 link	c.1053C>G	p.Ile351Met	missense_variant	Exon 8 of 14		NP_001136068.1	P13674-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA1	ENST00000394890.7 link	c.1053C>G	p.Ile351Met	missense_variant	Exon 8 of 15	1	NM_001017962.3	ENSP00000378353.2		P13674-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250292

AF XY:

0.00

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

85810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1110276

Other (OTH)

AF:

0.00

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.27

T;.;T;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.89

.;.;D;D;D

M_CAP

Benign

0.0069

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;L;L;L

PhyloP100

-0.19

PrimateAI

Benign

0.44

PROVEAN

Benign

0.020

N;N;N;N;N

REVEL

Benign

0.022

Sift

Benign

0.13

T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.0010

B;.;B;.;.

Vest4

0.39

MutPred

0.28

Gain of ubiquitination at K353 (P = 0.0653);Gain of ubiquitination at K353 (P = 0.0653);Gain of ubiquitination at K353 (P = 0.0653);Gain of ubiquitination at K353 (P = 0.0653);Gain of ubiquitination at K353 (P = 0.0653);

MVP

0.29

ClinPred

0.058

GERP RS

-0.84

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.045

gMVP

0.37

Mutation Taster

=94/6

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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10-73046949-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over