chr19-49861485-T-A

Position:

chr19-49861485-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007254.4(PNKP):c.1412A>T(p.His471Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000157 in 1,608,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.82

Variant links:

Genes affected

PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

PNKP links:

PNKP (HGNC:):

PNKP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4 linkuse as main transcript	c.1412A>T	p.His471Leu	missense_variant	16/17	ENST00000322344.8	NP_009185.2	Q96T60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 linkuse as main transcript	c.1412A>T	p.His471Leu	missense_variant	16/17	1	NM_007254.4	ENSP00000323511.2		Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.000157

AC:

AN:

146272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000700

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000632

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000208

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251278

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1461714

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000157

AC:

AN:

146334

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

70828

show subpopulations

Gnomad4 AFR

AF:

0.000128

Gnomad4 AMR

AF:

0.0000699

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000635

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000208

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000146

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 22508754) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.1412A>T (p.H471L) alteration is located in exon 16 (coding exon 15) of the PNKP gene. This alteration results from a A to T substitution at nucleotide position 1412, causing the histidine (H) at amino acid position 471 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 471 of the PNKP protein (p.His471Leu). This variant is present in population databases (rs142032281, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 206416). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PNKP protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Benign

0.93

DEOGEN2

Benign

0.38

T;T;T;T;T

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

.;T;T;T;T

M_CAP

Pathogenic

0.48

MetaRNN

Uncertain

0.48

T;T;T;T;T

MetaSVM

Benign

-0.52

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-9.0

D;.;.;.;.

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;.;.;.;.

Sift4G

Uncertain

0.0090

D;D;D;D;D

Polyphen

1.0

D;.;D;.;.

Vest4

0.66

MVP

0.73

MPC

0.53

ClinPred

0.71

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: -15

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