Genetic Variant P3H4:p.Arg340Trp (chr17-41807903-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006455.3(P3H4):c.1018C>T(p.Arg340Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

P3H4
NM_006455.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H4	NM_006455.3 link	c.1018C>T	p.Arg340Trp	missense_variant	Exon 5 of 8	ENST00000393928.6	NP_006446.1	Q92791
P3H4	XM_047435137.1 link	c.1201C>T	p.Arg401Trp	missense_variant	Exon 5 of 8		XP_047291093.1
P3H4	XM_047435138.1 link	c.1201C>T	p.Arg401Trp	missense_variant	Exon 5 of 7		XP_047291094.1
P3H4	XM_006721640.5 link	c.1018C>T	p.Arg340Trp	missense_variant	Exon 5 of 7		XP_006721703.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
P3H4	ENST00000393928.6 link	c.1018C>T	p.Arg340Trp	missense_variant	Exon 5 of 8	1	NM_006455.3	ENSP00000377505.1	Q92791
P3H4	ENST00000355468.7 link	c.1018C>T	p.Arg340Trp	missense_variant	Exon 6 of 9	2		ENSP00000347649.2	Q92791
P3H4	ENST00000592026.1 link	c.532C>T	p.Arg178Trp	missense_variant	Exon 4 of 5	5		ENSP00000468174.1	K7ERA3
P3H4	ENST00000587455.1 link	n.482-1024C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000558

AC:

AN:

250960

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000348

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:

0.0000151

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.000291

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111946

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1018C>T (p.R340W) alteration is located in exon 5 (coding exon 5) of the P3H4 gene. This alteration results from a C to T substitution at nucleotide position 1018, causing the arginine (R) at amino acid position 340 to be replaced by a tryptophan (W). 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

0.32

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

3.1

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.77

MutPred

0.55

Loss of disorder (P = 0.0589);Loss of disorder (P = 0.0589);

MVP

0.20

MPC

0.94

ClinPred

0.96

GERP RS

3.7

Varity_R

0.19

gMVP

0.65

Mutation Taster

=74/26

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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17-41807903-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over