16-56831918-C-T

Variant names:

• chr16-56831918-C-T
• rs145146218
• NM_014669.5:c.1162C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014669.5(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 NM_014669.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: 2.10
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 12

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09350121).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014669.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP93	NM_014669.5	MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 11 of 22	NP_055484.3
	NUP93	NM_001242795.2		c.793C>T	p.Arg265Trp	missense	Exon 9 of 20	NP_001229724.1
	NUP93	NM_001242796.2		c.793C>T	p.Arg265Trp	missense	Exon 9 of 20	NP_001229725.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP93	ENST00000308159.10	TSL:1 MANE Select	c.1162C>T	p.Arg388Trp	missense	Exon 11 of 22	ENSP00000310668.5
	NUP93	ENST00000569842.5	TSL:5	c.1162C>T	p.Arg388Trp	missense	Exon 11 of 23	ENSP00000458101.1
	NUP93	ENST00000542526.5	TSL:2	c.793C>T	p.Arg265Trp	missense	Exon 9 of 20	ENSP00000440235.1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152100 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.000720 AC: 181 AN: 251340 AF XY: 0.000780

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 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.: 2 Cov.: 31 AF XY: 0.000642 AC XY: 467 AN XY: 727230

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000927 AC: 80 AN: 86258

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53420

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000597 AC: 664 AN: 1111970

Other (OTH) AF: 0.000546 AC: 33 AN: 60396

GnomAD4 genome AF: 0.000710 AC: 108 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.000632 AC XY: 47 AN XY: 74420

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.000524 AC: 8 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000930 Hom.: 1

Bravo AF: 0.000491

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000840 AC: 102

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Nephrotic syndrome, type 12 Pathogenic:1 Uncertain:2

Nov 20, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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).

May 24, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Pathogenic:1 Uncertain:2

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Apr 08, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 39564605)

Nephrotic syndrome Pathogenic:1

May 08, 2019

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Sep 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.76
MPC		1.1
ClinPred		0.17	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.74
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs145146218; hg19: chr16-56865830;