Genetic Variant P3H4:p.Met383Ile (chr17-41803429-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006455.3(P3H4):c.1149G>A(p.Met383Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,374 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 (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

P3H4
NM_006455.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

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 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
P3H4	NM_006455.3 link	c.1149G>A	p.Met383Ile	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000393928.6	NP_006446.1	Q92791
P3H4	XM_047435137.1 link	c.1332G>A	p.Met444Ile	missense_variant, splice_region_variant	Exon 7 of 8		XP_047291093.1
P3H4	XM_047435138.1 link	c.1330-450G>A		intron_variant	Intron 6 of 6		XP_047291094.1
P3H4	XM_006721640.5 link	c.1147-450G>A		intron_variant	Intron 6 of 6		XP_006721703.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
P3H4	ENST00000393928.6 link	c.1149G>A	p.Met383Ile	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_006455.3	ENSP00000377505.1	Q92791
P3H4	ENST00000355468.7 link	c.1149G>A	p.Met383Ile	missense_variant, splice_region_variant	Exon 8 of 9	2		ENSP00000347649.2	Q92791
P3H4	ENST00000465097.1 link	n.54G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000435615.1	H0YED7
P3H4	ENST00000484247.1 link	n.698G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461374

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111744

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1149G>A (p.M383I) alteration is located in exon 7 (coding exon 7) of the P3H4 gene. This alteration results from a G to A substitution at nucleotide position 1149, causing the methionine (M) at amino acid position 383 to be replaced by an isoleucine (I). 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

Pathogenic

0.72

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.049

T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.67

.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;M

PhyloP100

4.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.095

Sift

Benign

0.35

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.89

P;P

Vest4

0.44

MutPred

0.24

Loss of phosphorylation at T388 (P = 0.0913);Loss of phosphorylation at T388 (P = 0.0913);

MVP

0.088

MPC

0.36

ClinPred

0.43

GERP RS

5.8

Varity_R

0.33

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -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