15-24676231-A-T

Variant summary

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

The NM_018958.3(NPAP1):​c.364A>T​(p.Met122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000584 in 1,370,196 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 (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

NPAP1
NM_018958.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.05
Variant links:
Genes affected
NPAP1 (HGNC:1190): (nuclear pore associated protein 1) This intronless retrogene is located in the Prader-Willi syndrome region on chromosome 15. This gene exhibits tissue-specific imprinting. Expression in adult testis and brain is biallelic, while expression in fetal brain is monoallelic and only from the paternal chromosome. The encoded protein is associated with the nuclear pore complex. [provided by RefSeq, Mar 2021]

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=0.033878177).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPAP1NM_018958.3 linkuse as main transcriptc.364A>T p.Met122Leu missense_variant 1/1 ENST00000329468.5 NP_061831.2 Q9NZP6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPAP1ENST00000329468.5 linkuse as main transcriptc.364A>T p.Met122Leu missense_variant 1/16 NM_018958.3 ENSP00000333735.3 Q9NZP6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000113
AC:
2
AN:
176582
Hom.:
0
AF XY:
0.0000215
AC XY:
2
AN XY:
93226
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000233
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000584
AC:
8
AN:
1370196
Hom.:
0
Cov.:
32
AF XY:
0.00000446
AC XY:
3
AN XY:
672414
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000799
Gnomad4 NFE exome
AF:
0.00000281
Gnomad4 OTH exome
AF:
0.0000178
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000167
AC:
2

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 submitterclinical testingAmbry GeneticsDec 08, 2023The c.364A>T (p.M122L) alteration is located in exon 1 (coding exon 1) of the NPAP1 gene. This alteration results from a A to T substitution at nucleotide position 364, causing the methionine (M) at amino acid position 122 to be replaced by a leucine (L). 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
Benign
-0.43
T
BayesDel_noAF
Benign
-0.81
CADD
Benign
1.4
DANN
Benign
0.42
DEOGEN2
Benign
0.0021
T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0050
N
LIST_S2
Benign
0.20
T
M_CAP
Benign
0.00042
T
MetaRNN
Benign
0.034
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.22
N
REVEL
Benign
0.0050
Sift
Benign
0.18
T
Sift4G
Benign
0.32
T
Polyphen
0.0
B
Vest4
0.098
MutPred
0.20
Gain of loop (P = 0.0435);
MVP
0.014
MPC
0.062
ClinPred
0.099
T
GERP RS
-3.8
Varity_R
0.069
gMVP
0.063

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.

Other links and lift over

dbSNP: rs776441508; hg19: chr15-24921378; API