Genetic Variant NM_006455.3:c.1258G>A (chr17-41803320-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.1258G>A(p.Glu420Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

P3H4
NM_006455.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64

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 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.1258G>A	p.Glu420Lys	missense_variant	Exon 7 of 8	ENST00000393928.6	NP_006446.1	Q92791
P3H4	XM_047435137.1 link	c.1441G>A	p.Glu481Lys	missense_variant	Exon 7 of 8		XP_047291093.1
P3H4	XM_047435138.1 link	c.1330-341G>A		intron_variant	Intron 6 of 6		XP_047291094.1
P3H4	XM_006721640.5 link	c.1147-341G>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.1258G>A	p.Glu420Lys	missense_variant	Exon 7 of 8	1	NM_006455.3	ENSP00000377505.1	Q92791
P3H4	ENST00000355468.7 link	c.1258G>A	p.Glu420Lys	missense_variant	Exon 8 of 9	2		ENSP00000347649.2	Q92791
P3H4	ENST00000465097.1 link	n.163G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000435615.1	H0YED7
P3H4	ENST00000484247.1 link	n.807G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111952

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1258G>A (p.E420K) 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 1258, causing the glutamic acid (E) at amino acid position 420 to be replaced by a lysine (K). 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

0.17

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

7.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0040

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.72

MutPred

0.27

Gain of ubiquitination at E420 (P = 0.0082);Gain of ubiquitination at E420 (P = 0.0082);

MVP

0.16

MPC

0.29

ClinPred

0.97

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.39

Mutation Taster

=66/34

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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NM_006455.3:c.1258G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over