9-137040843-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015392.4(NPDC1):​c.527G>A​(p.Arg176Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,596,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

NPDC1
NM_015392.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.265
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.040685117).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPDC1NM_015392.4 linkc.527G>A p.Arg176Gln missense_variant Exon 4 of 9 ENST00000371601.5 NP_056207.3 Q9NQX5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPDC1ENST00000371601.5 linkc.527G>A p.Arg176Gln missense_variant Exon 4 of 9 1 NM_015392.4 ENSP00000360660.4 Q9NQX5
NPDC1ENST00000371600.7 linkc.761G>A p.Arg254Gln missense_variant Exon 3 of 8 1 ENSP00000360659.3 Q5SPY9
NPDC1ENST00000488145.1 linkn.671G>A non_coding_transcript_exon_variant Exon 3 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152190
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000230
AC:
5
AN:
217764
Hom.:
0
AF XY:
0.0000251
AC XY:
3
AN XY:
119760
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000352
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000408
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000339
AC:
49
AN:
1444364
Hom.:
0
Cov.:
34
AF XY:
0.0000293
AC XY:
21
AN XY:
717866
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000255
Gnomad4 SAS exome
AF:
0.0000237
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000397
Gnomad4 OTH exome
AF:
0.0000334
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152308
Hom.:
0
Cov.:
33
AF XY:
0.0000806
AC XY:
6
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000831
ExAC
AF:
0.0000335
AC:
4
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 25, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.527G>A (p.R176Q) alteration is located in exon 4 (coding exon 4) of the NPDC1 gene. This alteration results from a G to A substitution at nucleotide position 527, causing the arginine (R) at amino acid position 176 to be replaced by a glutamine (Q). 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
0.075
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
14
DANN
Uncertain
0.97
DEOGEN2
Benign
0.13
.;T
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.051
N
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.0093
T
MetaRNN
Benign
0.041
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
.;L
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.89
N;N
REVEL
Benign
0.064
Sift
Benign
0.15
T;T
Sift4G
Benign
0.16
T;T
Polyphen
0.67
P;B
Vest4
0.22
MVP
0.043
MPC
0.094
ClinPred
0.044
T
GERP RS
0.068
Varity_R
0.056
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs566074540; hg19: chr9-139935295; API