chr19-45152734-C-T

Position:

chr19-45152734-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198478.4(NKPD1):c.1703G>A(p.Gly568Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,584,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

NKPD1
NM_198478.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.635

Variant links:

Genes affected

NKPD1 (HGNC:24739): (NTPase KAP family P-loop domain containing 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

NKPD1 links:

MARK4 (HGNC:13538): (microtubule affinity regulating kinase 4) This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer's disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

MARK4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09851563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NKPD1	NM_198478.4 linkuse as main transcript	c.1703G>A	p.Gly568Asp	missense_variant	5/5	ENST00000686631.1
NKPD1	XM_011526799.3 linkuse as main transcript	c.1784G>A	p.Gly595Asp	missense_variant	5/5
NKPD1	XM_011526804.3 linkuse as main transcript	c.1346G>A	p.Gly449Asp	missense_variant	4/4
NKPD1	XM_011526805.3 linkuse as main transcript	c.1178G>A	p.Gly393Asp	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NKPD1	ENST00000686631.1 linkuse as main transcript	c.1703G>A	p.Gly568Asp	missense_variant	5/5		NM_198478.4	P2
NKPD1	ENST00000317951.6 linkuse as main transcript	c.1703G>A	p.Gly568Asp	missense_variant	5/5	2		P2
NKPD1	ENST00000589776.1 linkuse as main transcript	c.1037G>A	p.Gly346Asp	missense_variant	1/1			A2
MARK4	ENST00000587566.5 linkuse as main transcript	c.-277+73357C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.00000559

AC:

AN:

1432124

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

710958

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000472

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000273

Gnomad4 OTH exome

AF:

0.0000507

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000955

Bravo

AF:

0.0000718

ExAC

AF:

0.00000851

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.1703G>A (p.G568D) alteration is located in exon 4 (coding exon 4) of the NKPD1 gene. This alteration results from a G to A substitution at nucleotide position 1703, causing the glycine (G) at amino acid position 568 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.5

DANN

Benign

0.95

DEOGEN2

Benign

0.0011

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.031

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.099

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.41

N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.59

REVEL

Benign

0.039

Polyphen

0.44

B;B

Vest4

0.047

MutPred

0.42

Loss of catalytic residue at G346 (P = 0.0278);Loss of catalytic residue at G346 (P = 0.0278);

MVP

0.16

MPC

0.95

ClinPred

0.20

GERP RS

-0.12

Varity_R

0.19

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over