rs3739203

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007254.4(PNKP):​c.1127-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,614,094 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0087 ( 7 hom., cov: 32)
Exomes 𝑓: 0.0088 ( 79 hom. )

Consequence

PNKP
NM_007254.4 splice_region, intron

Scores

2
Splicing: ADA: 0.01320
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.562
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
Variant 19-49862113-G-A is Benign according to our data. Variant chr19-49862113-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49862113-G-A is described in Lovd as [Likely_benign]. Variant chr19-49862113-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00868 (1322/152272) while in subpopulation AMR AF = 0.00993 (152/15302). AF 95% confidence interval is 0.00902. There are 7 homozygotes in GnomAd4. There are 566 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PNKPNM_007254.4 linkc.1127-8C>T splice_region_variant, intron_variant Intron 12 of 16 ENST00000322344.8 NP_009185.2 Q96T60-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PNKPENST00000322344.8 linkc.1127-8C>T splice_region_variant, intron_variant Intron 12 of 16 1 NM_007254.4 ENSP00000323511.2 Q96T60-1

Frequencies

GnomAD3 genomes
AF:
0.00870
AC:
1323
AN:
152154
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00949
Gnomad AMI
AF:
0.0373
Gnomad AMR
AF:
0.00995
Gnomad ASJ
AF:
0.0121
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.00104
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.00963
Gnomad OTH
AF:
0.0110
GnomAD2 exomes
AF:
0.00674
AC:
1695
AN:
251374
AF XY:
0.00650
show subpopulations
Gnomad AFR exome
AF:
0.00942
Gnomad AMR exome
AF:
0.00607
Gnomad ASJ exome
AF:
0.00943
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00194
Gnomad NFE exome
AF:
0.00954
Gnomad OTH exome
AF:
0.0112
GnomAD4 exome
AF:
0.00878
AC:
12839
AN:
1461822
Hom.:
79
Cov.:
34
AF XY:
0.00861
AC XY:
6259
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.0104
AC:
349
AN:
33480
Gnomad4 AMR exome
AF:
0.00604
AC:
270
AN:
44722
Gnomad4 ASJ exome
AF:
0.0103
AC:
269
AN:
26132
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.00146
AC:
126
AN:
86258
Gnomad4 FIN exome
AF:
0.00215
AC:
115
AN:
53416
Gnomad4 NFE exome
AF:
0.00993
AC:
11037
AN:
1111952
Gnomad4 Remaining exome
AF:
0.00997
AC:
602
AN:
60394
Heterozygous variant carriers
0
739
1478
2216
2955
3694
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
416
832
1248
1664
2080
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00868
AC:
1322
AN:
152272
Hom.:
7
Cov.:
32
AF XY:
0.00760
AC XY:
566
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.00948
AC:
0.00948438
AN:
0.00948438
Gnomad4 AMR
AF:
0.00993
AC:
0.00993334
AN:
0.00993334
Gnomad4 ASJ
AF:
0.0121
AC:
0.0121107
AN:
0.0121107
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000828
AC:
0.000828157
AN:
0.000828157
Gnomad4 FIN
AF:
0.00104
AC:
0.00103539
AN:
0.00103539
Gnomad4 NFE
AF:
0.00963
AC:
0.00963094
AN:
0.00963094
Gnomad4 OTH
AF:
0.0109
AC:
0.0108798
AN:
0.0108798
Heterozygous variant carriers
0
66
133
199
266
332
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00933
Hom.:
3
Bravo
AF:
0.00940
Asia WGS
AF:
0.00115
AC:
4
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Microcephaly, seizures, and developmental delay Benign:4
May 31, 2017
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 09, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:4
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jan 26, 2018
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PNKP: BP4, BS2 -

not specified Benign:3
Nov 27, 2012
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 11, 2015
Genetic Services Laboratory, University of Chicago
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 11, 2012
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Developmental and epileptic encephalopathy, 12 Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.73
CADD
Benign
5.8
DANN
Benign
0.91
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.013
dbscSNV1_RF
Benign
0.080
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3739203; hg19: chr19-50365370; API