rs750224965

Variant names:

• chr19-49862702-T-A
• rs750224965
• NM_007254.4:c.853A>T
• PNKP p.Ile285Phe

Your query was ambiguous. Multiple possible variants found:

• chr19-49862702-T-A
• chr19-49862702-T-C

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_007254.4(PNKP):c.853A>T (p.Ile285Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I285M: Uncertain_significance (ClinVar VariationId 1763848, 1 star); p.I285V: Uncertain_significance (ClinVar VariationId 199124, 2 stars)

• Frequency: Genomes: not found (cov: 33)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.03
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ataxia - oculomotor apraxia type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, G2P, PanelApp Australia
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Charcot-Marie-Tooth disease type 2B2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 0 points.

• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00178) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007254.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	NM_007254.4	MANE Select	c.853A>T	p.Ile285Phe	missense	Exon 9 of 17	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.853A>T	p.Ile285Phe	missense	Exon 9 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.853A>T	p.Ile285Phe	missense	Exon 8 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*780A>T		3_prime_UTR	Exon 8 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Case/control cohorts

Cohort

Cases

Controls

SCHEMA (Schizophrenia)

3 / 48330AF: 0.0000620732

2 / 74318AF: 0.0000269114

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.099
DANN	Benign	0.75
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.041	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.84	N
PhyloP100		-2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	3.3	N
REVEL	Benign	0.095
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
popEVE	Benign	-2.4
VESM-3B	Benign	-6.9
FuncVEP CTI	Benign	0.017
AlphaGenome AVI	Benign	1.5
GPN-Star LLR		-3.2
GPN-Star score		3.2
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2
Pangolin (max)	Benign	0.040

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs750224965;

hg19: chr19-50365959;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar