16-56831918-C-T

Position:

chr16-56831918-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000308159.10(NUP93):c.1162C>T(p.Arg388Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,614,068 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00071 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 2 hom. )

Consequence

NUP93
ENST00000308159.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 2.10

Variant links:

Genes affected

NUP93 (HGNC:28958): (nucleoporin 93) 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. This gene encodes a nucleoporin protein that localizes both to the basket of the pore and to the nuclear entry of the central gated channel of the pore. The encoded protein is a target of caspase cysteine proteases that play a central role in programmed cell death by apoptosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

NUP93 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09350121).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NUP93	NM_014669.5 linkuse as main transcript	c.1162C>T	p.Arg388Trp	missense_variant	11/22	ENST00000308159.10	NP_055484.3
NUP93	NM_001242795.2 linkuse as main transcript	c.793C>T	p.Arg265Trp	missense_variant	9/20		NP_001229724.1
NUP93	NM_001242796.2 linkuse as main transcript	c.793C>T	p.Arg265Trp	missense_variant	9/20		NP_001229725.1
NUP93	XM_005256263.4 linkuse as main transcript	c.1162C>T	p.Arg388Trp	missense_variant	11/22		XP_005256320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUP93	ENST00000308159.10 linkuse as main transcript	c.1162C>T	p.Arg388Trp	missense_variant	11/22	1	NM_014669.5	ENSP00000310668	P1	Q8N1F7-1

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000720

AC:

181

AN:

251340

Hom.:

AF XY:

0.000780

AC XY:

106

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.000968

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000566

AC:

828

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000642

AC XY:

467

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000927

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.000597

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000710

AC:

108

AN:

152218

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00121

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000958

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000840

AC:

102

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000818

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Nephrotic syndrome, type 12

Pathogenic:1Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	May 24, 2023	This sequence variant is a single nucleotide substitution (C>T) at coding position 1162 in the NUP93 gene which results in an arginine to tryptophan amino acid change at residue 388 in the NUP93 protein. This is a previously reported variant (ClinVar) which has been observed in compound heterozygous state with a known pathogenic NUP93 variant in an individual with steroid-resistant nephrotic syndrome (PMID: 26878725). This variant is present in 221/282730 alleles (0.08%) in the gnomAD population database, including 1 homozygote. Multiple bioinformatic tools queried predict that this amino acid change would be damaging, and arginine is highly conserved at this protein position in vertebrates. In vitro functiol studies indicated that the variant protein was not able to rescue nuclear pore complex formation detect in Nup93-depleted Xenopus laevis egg extract (PMID: 26878725); additiolly, expression of the variant protein in HEK293 NUP93-shR treated cells was not able restore SMAD4 sigling. Despite these functiol studies, the precise physiological consequence of this variant is unclear. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider it to be a variant of uncertain significance. ACMG Criteria: PM3, PP3, PS3 -
Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Arg388Trp variant in NUP93 was identified by our study in one individual in the compound heterozygous state, with another VUS, with nephrotic syndrome. This variant was seen in 0.08230% (228/277052) of chromosomes, including one individual in the homozygous state, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145146218). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported pathogenic by OMIM in ClinVar (Variation ID: 224968). The p.Arg388Trp variant in NUP93 has been reported in one Serbian individual in the compound heterozygous state, with another missense variant reported pathogenic by OMIM in ClinVar (Variation ID: 224964), with nephrotic syndrome. In vitro functional studies with Xenopus laevis egg extracts and other assays provide some evidence that the p.Arg388Trp variant may impact nuclear pore complex formation and SMAD protein signalling (PMID: 26878725). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of the p.Arg388Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PS3_Moderate (Richards 2015). -

not provided

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 388 of the NUP93 protein (p.Arg388Trp). This variant is present in population databases (rs145146218, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 26878725). ClinVar contains an entry for this variant (Variation ID: 224968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NUP93 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NUP93 function (PMID: 26878725). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2024	Published functional studies demonstrated that R388W mutant failed to restore nuclear envelope and NPC assembly when added back to Xenopus laevis egg extracts lacking NUP93 protein (PMID: 26878725); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30741391, 29869118, 34426522, 26878725, 37692026, 37873737, 35026467, 38547852, 37762751, 38383349) -

Nephrotic syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

May 08, 2019

This individual is heterozygous for the c.1162C>T variant in the NUP93 gene, which results in the amino acid substitution of arginine to tryptophan at residue 388, p.(Arg388Trp). This variant has been reported as compound heterozygous with a second pathogenic NUP93 variant in an individual with steroid-resistant nephrotic sydrome (Braun et al 2016 Nat Genet. 48: 457-465). In vitro functional studies is supportive of a damaging effect from this amino acid change (Braun et al 2016). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.078% (221 out of 282,730 alleles including 1 homozygote). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be likely pathogenic according to the ACMG guidelines. (Evidence used: PS3, PM2, PM3, PP3) -

NUP93-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 07, 2023

The NUP93 c.1162C>T variant is predicted to result in the amino acid substitution p.Arg388Trp. This variant has been reported in the compound heterozygous state in a patient with steroid-resistant nephrotic syndrome, and segregated with disease in this family (Braun et al. 2016. PubMed ID: 26878725). In vitro functional studies indicated that this variant caused disrupted assembly of nuclear pore complex (Braun et al. 2016. PubMed ID: 26878725). However, this variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD, including 1 homozygous individual (http://gnomad.broadinstitute.org/variant/16-56865830-C-T). In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/224968/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;T;T;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D;D;.;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.094

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.7

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.0

D;D;D;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MVP

0.76

MPC

1.1

ClinPred

0.17

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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