rs3739203

chr19-49862113-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007254.4(PNKP):c.1127-8C>T variant causes a splice region, splice polypyrimidine tract, 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. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (79 hom.)
• Consequence: PNKP NM_007254.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01320
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.562

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]

ACMG classification

Verdict is Benign. Variant got -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 [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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKP	NM_007254.4	c.1127-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000322344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKP	ENST00000322344.8	c.1127-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007254.4	P1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1323 AN: 152154 Hom.: 7 Cov.: 32

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

GnomAD3 exomes AF: 0.00674 AC: 1695 AN: 251374 Hom.: 10 AF XY: 0.00650 AC XY: 883 AN XY: 135874

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 SAS exome AF: 0.00134

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

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00993

Gnomad4 OTH exome AF: 0.00997

GnomAD4 genome AF: 0.00868 AC: 1322 AN: 152272 Hom.: 7 Cov.: 32 AF XY: 0.00760 AC XY: 566 AN XY: 74452

Gnomad4 AFR AF: 0.00948

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00963

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00924 Hom.: 3

Bravo AF: 0.00940

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, seizures, and developmental delay Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 27, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2012	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PNKP: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2018	- -

Developmental and epileptic encephalopathy, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

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

Other links and lift over

dbSNP: rs3739203; hg19: chr19-50365370;