Genetic Variant PNKP:p.Gly375Trp (chr19-49862188-C-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_007254.4(PNKP):c.1123G>T(p.Gly375Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.41

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.929

PP5

Variant 19-49862188-C-A is Pathogenic according to our data. Variant chr19-49862188-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 187766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49862188-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4 link	c.1123G>T	p.Gly375Trp	missense_variant	Exon 12 of 17	ENST00000322344.8	NP_009185.2	Q96T60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 link	c.1123G>T	p.Gly375Trp	missense_variant	Exon 12 of 17	1	NM_007254.4	ENSP00000323511.2		Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia - oculomotor apraxia type 4

Pathogenic:3

Mar 05, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2023

Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 31, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PNKP c.1123G>T (p.Gly375Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250354 control chromosomes. c.1123G>T has been reported in the literature in multiple individuals affected with Ataxia - oculomotor apraxia type 4 (e.g. Bras_2015). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 25728773). ClinVar contains an entry for this variant (Variation ID: 187766). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Jan 22, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in a patient with pure ataxia who also harbored a second likely pathogenic variant (phase unknown) (PMID: 33956305); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29652299, 22508754, 33332469, 33956305, 35187769, 31707899, 38266593, 25728773, 35426160) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Feb 22, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly, seizures, and developmental delay

Pathogenic:1

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1123G>T;p.(Gly375Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 187766; OMIM: 605610.0005; PMID: 32010037; 32347949; 31061747; 31436889; 27890643; 27125728; 29652299; 25728773) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (AAA_33 domain) - PM1. The variant is present at low allele frequencies population databases (rs786203983– gnomAD 0.0003943%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly375Trp) was detected in trans with a pathogenic variant (PMID: 31061747; 31436889; 27890643; 25728773) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID 25728773) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Developmental and epileptic encephalopathy, 12

Pathogenic:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 375 of the PNKP protein (p.Gly375Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia with oculomotor apraxia (PMID: 25728773, 31061747). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 187766). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PNKP protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;D;T;D;T

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

D;.;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.2

.;M;.;M;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.1

.;D;.;.;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

.;D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;D;.;D;.

Vest4

0.79

MutPred

0.67

Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;Loss of loop (P = 0.0203);.;

MVP

0.99

MPC

0.52

ClinPred

0.99

GERP RS

4.8

Varity_R

0.87

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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