rs3739177

chr19-49865596-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007254.4(PNKP):c.199-170G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0749 in 547,908 control chromosomes in the GnomAD database, including 1,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.070 (376 hom., cov: 30)
  • Exomes 𝑓: 0.077 (1390 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.43

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-49865596-C-T is Benign according to our data. Variant chr19-49865596-C-T is described in ClinVar as [Benign]. Clinvar id is 667945.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0805 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKP	NM_007254.4	c.199-170G>A		intron_variant		ENST00000322344.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKP	ENST00000322344.8	c.199-170G>A		intron_variant		1	NM_007254.4	P1

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10200 AN: 146068 Hom.: 376 Cov.: 30

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.0280

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0711

Gnomad EAS AF: 0.000789

Gnomad SAS AF: 0.0829

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.0823

Gnomad OTH AF: 0.0609

GnomAD4 exome AF: 0.0768 AC: 30846 AN: 401774 Hom.: 1390 AF XY: 0.0774 AC XY: 16320 AN XY: 210728

Gnomad4 AFR exome AF: 0.0659

Gnomad4 AMR exome AF: 0.0527

Gnomad4 ASJ exome AF: 0.0723

Gnomad4 EAS exome AF: 0.000253

Gnomad4 SAS exome AF: 0.0929

Gnomad4 FIN exome AF: 0.0670

Gnomad4 NFE exome AF: 0.0857

Gnomad4 OTH exome AF: 0.0785

GnomAD4 genome AF: 0.0698 AC: 10199 AN: 146134 Hom.: 376 Cov.: 30 AF XY: 0.0688 AC XY: 4866 AN XY: 70736

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.0612

Gnomad4 ASJ AF: 0.0711

Gnomad4 EAS AF: 0.000791

Gnomad4 SAS AF: 0.0835

Gnomad4 FIN AF: 0.0525

Gnomad4 NFE AF: 0.0823

Gnomad4 OTH AF: 0.0603

Alfa AF: 0.0791 Hom.: 98

Bravo AF: 0.0674

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.3
Dann	Benign	0.59

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

LitVar

Other links and lift over

dbSNP: rs3739177; hg19: chr19-50368853;