PNKP p.Phe327Leu

Variant names:

• chr19-49862419-G-T
• NM_007254.4:c.981C>A
• PNKP p.Phe327Leu

Your query was ambiguous. Multiple possible variants found:

• chr19-49862419-G-T
• chr19-49862419-G-C
• chr19-49862421-A-G
• chr19-49862419-GAA-AAG
• chr19-49862419-GAA-TAG
• chr19-49862419-GAA-CAG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_007254.4(PNKP):​c.981C>A​(p.Phe327Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.788
• 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, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
• microcephaly, seizures, and developmental delay

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_007254.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	NM_007254.4	MANE Select	c.981C>A	p.Phe327Leu	missense	Exon 11 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.981C>A	p.Phe327Leu	missense	Exon 11 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.981C>A	p.Phe327Leu	missense	Exon 10 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*908C>A		non_coding_transcript_exon	Exon 10 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422884 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 704130

African (AFR) AF: 0.00 AC: 0 AN: 32684

American (AMR) AF: 0.00 AC: 0 AN: 38900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25402

East Asian (EAS) AF: 0.00 AC: 0 AN: 37716

South Asian (SAS) AF: 0.00 AC: 0 AN: 81312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092104

Other (OTH) AF: 0.00 AC: 0 AN: 58866

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.79
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.40
Sift	Benign	0.092	T
Sift4G	Uncertain	0.011	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.80
Mutation Taster		=65/35	polymorphism

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

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

Other links and lift over

hg19: chr19-50365676;