Genetic Variant NPDC1:p.Ala198Thr (chr9-137040702-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_015392.4(NPDC1):c.592G>A(p.Ala198Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,586,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

NPDC1
NM_015392.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

NPDC1 (HGNC:7899): (neural proliferation, differentiation and control 1) Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

NPDC1 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=0.2128711).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPDC1	NM_015392.4 link	c.592G>A	p.Ala198Thr	missense_variant	Exon 5 of 9	ENST00000371601.5	NP_056207.3	Q9NQX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPDC1	ENST00000371601.5 link	c.592G>A	p.Ala198Thr	missense_variant	Exon 5 of 9	1	NM_015392.4	ENSP00000360660.4	Q9NQX5
NPDC1	ENST00000371600.7 link	c.826G>A	p.Ala276Thr	missense_variant	Exon 4 of 8	1		ENSP00000360659.3	Q5SPY9
NPDC1	ENST00000488145.1 link	n.*111G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000114

AC:

AN:

202594

Hom.:

AF XY:

0.0000996

AC XY:

AN XY:

110460

show subpopulations

Gnomad AFR exome

AF:

0.000235

Gnomad AMR exome

AF:

0.0000335

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.000194

GnomAD4 exome

AF:

0.0000300

AC:

AN:

1434158

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

711926

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000245

Gnomad4 ASJ exome

AF:

0.0000391

Gnomad4 EAS exome

AF:

0.000462

Gnomad4 SAS exome

AF:

0.0000361

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000815

Gnomad4 OTH exome

AF:

0.000151

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000586

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.592G>A (p.A198T) alteration is located in exon 5 (coding exon 5) of the NPDC1 gene. This alteration results from a G to A substitution at nucleotide position 592, causing the alanine (A) at amino acid position 198 to be replaced by a threonine (T). 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

0.14

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;D

Eigen

Benign

0.020

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.6

.;M

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.19

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;D

Vest4

0.57

MVP

0.26

MPC

0.39

ClinPred

0.19

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.21

gMVP

0.29

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