Genetic Variant P4HTM:p.Ser189Arg (chr3-49001568-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_177939.3(P4HTM):c.567C>G(p.Ser189Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

P4HTM
NM_177939.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61

Variant links:

Genes affected

P4HTM (HGNC:28858): (prolyl 4-hydroxylase, transmembrane) The product of this gene belongs to the family of prolyl 4-hydroxylases. This protein is a prolyl hydroxylase that may be involved in the degradation of hypoxia-inducible transcription factors under normoxia. It plays a role in adaptation to hypoxia and may be related to cellular oxygen sensing. Alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

P4HTM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HTM	NM_177939.3 link	c.567C>G	p.Ser189Arg	missense_variant	Exon 3 of 9	ENST00000383729.9	NP_808808.1	Q9NXG6-1
P4HTM	NM_177938.2 link	c.567C>G	p.Ser189Arg	missense_variant	Exon 3 of 9		NP_808807.2	Q9NXG6-3
P4HTM	XM_047448367.1 link	c.567C>G	p.Ser189Arg	missense_variant	Exon 3 of 5		XP_047304323.1
P4HTM	XR_007095696.1 link	n.583C>G		non_coding_transcript_exon_variant	Exon 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HTM	ENST00000383729.9 link	c.567C>G	p.Ser189Arg	missense_variant	Exon 3 of 9	1	NM_177939.3	ENSP00000373235.4		Q9NXG6-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249854

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.0000620

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461368

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.567C>G (p.S189R) alteration is located in exon 3 (coding exon 3) of the P4HTM gene. This alteration results from a C to G substitution at nucleotide position 567, causing the serine (S) at amino acid position 189 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

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

0.097

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.52

Sift

Benign

0.061

T;T

Sift4G

Benign

0.082

T;T

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.46

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.72

MPC

0.62

ClinPred

0.53

GERP RS

5.9

Varity_R

0.49

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over