19-49908289-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_016553.5(NUP62):​c.1519G>A​(p.Glu507Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,874 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E507V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NUP62
NM_016553.5 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.18
Variant links:
Genes affected
NUP62 (HGNC:8066): (nucleoporin 62) The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene is a member of the FG-repeat containing nucleoporins and is localized to the nuclear pore central plug. This protein associates with the importin alpha/beta complex which is involved in the import of proteins containing nuclear localization signals. Multiple transcript variants of this gene encode a single protein isoform. [provided by RefSeq, Jul 2008]
IL4I1 (HGNC:19094): (interleukin 4 induced 1) This gene encodes a secreted L-amino acid oxidase protein which primarily catabolizes L-phenylalanine and, to a lesser extent, L-arginine. The expression of this gene is induced by the cytokine interleukin 4 in B cells. This gene is also expressed in macrophages and dendritic cells. This protein may play a role immune system escape as it is expressed in tumor-associated macrophages and suppresses T-cell responses. This protein also contains domains thought to be involved in the binding of flavin adenine dinucleotide (FAD) cofactor. Multiple transcript variants encoding different isoforms have been found for this gene. Some transcripts of this gene share a promoter and exons of the 5' UTR with the overlapping NUP62 gene. [provided by RefSeq, Jul 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32891214).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NUP62NM_016553.5 linkc.1519G>A p.Glu507Lys missense_variant Exon 3 of 3 ENST00000352066.8 NP_057637.2 P37198A0A024QZF1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NUP62ENST00000352066.8 linkc.1519G>A p.Glu507Lys missense_variant Exon 3 of 3 1 NM_016553.5 ENSP00000305503.3 P37198

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250422
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135508
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461692
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727164
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74324
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
May 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 507 of the NUP62 protein (p.Glu507Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NUP62-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Benign
-0.051
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.36
T;T;T;.;T
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
.;.;.;D;D
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.33
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L;L;.;L
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-2.9
D;D;.;.;.
REVEL
Benign
0.13
Sift
Uncertain
0.0070
D;D;.;.;.
Sift4G
Benign
0.096
T;T;T;T;T
Polyphen
0.64
P;P;P;.;P
Vest4
0.34
MutPred
0.34
Gain of methylation at E507 (P = 0.0014);Gain of methylation at E507 (P = 0.0014);Gain of methylation at E507 (P = 0.0014);.;Gain of methylation at E507 (P = 0.0014);
MVP
0.64
MPC
0.35
ClinPred
0.95
D
GERP RS
4.2
Varity_R
0.24
gMVP
0.33

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: rs1389217785; hg19: chr19-50411546; COSMIC: COSV61311921; COSMIC: COSV61311921; API