rs3739203

Variant names:

• chr19-49862113-G-A
• rs3739203
• NM_007254.4:c.1127-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49862113-G-A
• chr19-49862113-G-C

Variant summary

Our verdict is Benign. The variant received -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, 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: Splicing: ADA: 0.01320
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.562
• Publications: 3 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: Laboratory for Molecular Medicine, G2P, Orphanet
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: 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 Benign/Likely_benign. ClinVar VariationId is 95476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.1127-8C>T		splice_region intron	N/A	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.1127-8C>T		splice_region intron	N/A	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.1127-8C>T		splice_region intron	N/A	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*1054-8C>T		splice_region intron	N/A	ENSP00000468896.1	M0QX49

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

GnomAD2 exomes AF: 0.00674 AC: 1695 AN: 251374 AF XY: 0.00650

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

African (AFR) AF: 0.0104 AC: 349 AN: 33480

American (AMR) AF: 0.00604 AC: 270 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 269 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86258

European-Finnish (FIN) AF: 0.00215 AC: 115 AN: 53416

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.00993 AC: 11037 AN: 1111952

Other (OTH) AF: 0.00997 AC: 602 AN: 60394

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

African (AFR) AF: 0.00948 AC: 394 AN: 41542

American (AMR) AF: 0.00993 AC: 152 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00963 AC: 655 AN: 68010

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00933 Hom.: 3

Bravo AF: 0.00940

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephaly, seizures, and developmental delay (4)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Developmental and epileptic encephalopathy, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.8
DANN	Benign	0.91
PhyloP100		0.56
PromoterAI		0.0014	Neutral
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

Other links and lift over

dbSNP: rs3739203; hg19: chr19-50365370;