Genetic Variant NPDC1:p.Arg136Gln (chr9-137040963-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015392.4(NPDC1):c.407G>A(p.Arg136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,392,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

NPDC1
NM_015392.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.15

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039931506).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015392.4. 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
	NPDC1	NM_015392.4	MANE Select	c.407G>A	p.Arg136Gln	missense	Exon 4 of 9	NP_056207.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPDC1	ENST00000371601.5	TSL:1 MANE Select	c.407G>A	p.Arg136Gln	missense	Exon 4 of 9	ENSP00000360660.4	Q9NQX5
NPDC1	ENST00000371600.7	TSL:1	c.641G>A	p.Arg214Gln	missense	Exon 3 of 8	ENSP00000360659.3	Q5SPY9
NPDC1	ENST00000952624.1		c.407G>A	p.Arg136Gln	missense	Exon 4 of 9	ENSP00000622683.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000375

AC:

AN:

186602

AF XY:

0.0000396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000432

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000187

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000340

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1392042

Hom.:

Cov.:

AF XY:

0.0000219

AC XY:

AN XY:

686154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30880

American (AMR)

AF:

0.0000307

AC:

AN:

32546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21542

East Asian (EAS)

AF:

0.000102

AC:

AN:

39094

South Asian (SAS)

AF:

0.0000397

AC:

AN:

75486

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.00000926

AC:

AN:

1080368

Other (OTH)

AF:

0.0000349

AC:

AN:

57278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.73

CADD

Benign

3.7

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.094

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.66

M_CAP

Benign

0.011

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

-3.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.80

REVEL

Benign

0.026

Sift

Benign

0.084

Sift4G

Benign

0.38

Polyphen

0.060

Vest4

0.11

MutPred

0.53

Loss of methylation at R214 (P = 0.0143)

MVP

0.043

MPC

0.083

ClinPred

0.025

GERP RS

-6.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.30

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over