Genetic Variant P4HTM:p.Phe67Leu (chr3-48990457-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_177939.3(P4HTM):c.201C>A(p.Phe67Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

P4HTM
NM_177939.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.525

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38311538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HTM	NM_177939.3 link	c.201C>A	p.Phe67Leu	missense_variant	Exon 1 of 9	ENST00000383729.9	NP_808808.1	Q9NXG6-1
P4HTM	NM_177938.2 link	c.201C>A	p.Phe67Leu	missense_variant	Exon 1 of 9		NP_808807.2	Q9NXG6-3
P4HTM	XM_047448367.1 link	c.201C>A	p.Phe67Leu	missense_variant	Exon 1 of 5		XP_047304323.1
P4HTM	XR_007095696.1 link	n.217C>A		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HTM	ENST00000383729.9 link	c.201C>A	p.Phe67Leu	missense_variant	Exon 1 of 9	1	NM_177939.3	ENSP00000373235.4		Q9NXG6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000421

AC:

AN:

237442

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130292

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:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458486

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725612

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000835

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 12, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;T

Eigen

Benign

0.013

Eigen_PC

Benign

0.030

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.77

T;T;T

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.9

N;N;.

REVEL

Uncertain

0.52

Sift

Uncertain

0.021

D;D;.

Sift4G

Uncertain

0.033

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.49

MutPred

0.36

Loss of catalytic residue at F67 (P = 0.082);Loss of catalytic residue at F67 (P = 0.082);.;

MVP

0.64

MPC

2.3

ClinPred

0.94

GERP RS

3.4

Varity_R

0.56

gMVP

0.46

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over