Genetic Variant P3H4:p.Pro434Leu (chr17-41802970-G-A) – 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_006455.3(P3H4):c.1301C>T(p.Pro434Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

P3H4
NM_006455.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

Publications

0 publications found

Variant links:

Genes affected

P3H4 (HGNC:16946): (prolyl 3-hydroxylase family member 4 (inactive)) This nucleolar protein was first characterized because it was an autoantigen in cases on interstitial cystitis. The protein, with a predicted molecular weight of 50 kDa, appears to be localized in the particulate compartment of the interphase nucleolus, with a distribution distinct from that of nucleolar protein B23. During mitosis it is associated with chromosomes. [provided by RefSeq, Jul 2008]

P3H4 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=0.20231152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H4	NM_006455.3 link	c.1301C>T	p.Pro434Leu	missense_variant	Exon 8 of 8	ENST00000393928.6	NP_006446.1	Q92791
P3H4	XM_047435137.1 link	c.1484C>T	p.Pro495Leu	missense_variant	Exon 8 of 8		XP_047291093.1
P3H4	XM_047435138.1 link	c.1339C>T	p.Leu447Leu	synonymous_variant	Exon 7 of 7		XP_047291094.1
P3H4	XM_006721640.5 link	c.1156C>T	p.Leu386Leu	synonymous_variant	Exon 7 of 7		XP_006721703.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
P3H4	ENST00000393928.6 link	c.1301C>T	p.Pro434Leu	missense_variant	Exon 8 of 8	1	NM_006455.3	ENSP00000377505.1	Q92791
P3H4	ENST00000355468.7 link	c.1301C>T	p.Pro434Leu	missense_variant	Exon 9 of 9	2		ENSP00000347649.2	Q92791
P3H4	ENST00000465097.1 link	n.206C>T		non_coding_transcript_exon_variant	Exon 3 of 4	5		ENSP00000435615.1	H0YED7
P3H4	ENST00000484247.1 link	n.850C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

244870

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1301C>T (p.P434L) alteration is located in exon 8 (coding exon 8) of the P3H4 gene. This alteration results from a C to T substitution at nucleotide position 1301, causing the proline (P) at amino acid position 434 to be replaced by a leucine (L). 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

Benign

0.096

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.60

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

L;L

PhyloP100

3.7

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.19

Sift

Benign

0.090

T;T

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;D

Vest4

0.26

MutPred

0.14

Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);

MVP

0.44

MPC

0.26

ClinPred

0.52

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.17

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over