chr16-56834768-G-T

Variant names:

• chr16-56834768-G-T
• rs145473779
• NM_014669.5:c.1772G>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_014669.5(NUP93):​c.1772G>T​(p.Gly591Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,611,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002043967: Published functional studies suggest a damaging effect" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NUP93 NM_014669.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.44
• Publications: 19 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: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002043967: Published functional studies suggest a damaging effect; this variant fails to interact and reduces translocation of SMAD4 (PMID: 26878725); SCV002233611: Experimental studies have shown that this missense change affects NUP93 function (PMID: 26878725).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-56834768-G-T is Pathogenic according to our data. Variant chr16-56834768-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP93	NM_014669.5	MANE Select	c.1772G>T	p.Gly591Val	missense	Exon 16 of 22	NP_055484.3
	NUP93	NM_001242795.2		c.1403G>T	p.Gly468Val	missense	Exon 14 of 20	NP_001229724.1	Q8N1F7-2
	NUP93	NM_001242796.2		c.1403G>T	p.Gly468Val	missense	Exon 14 of 20	NP_001229725.1	Q8N1F7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP93	ENST00000308159.10	TSL:1 MANE Select	c.1772G>T	p.Gly591Val	missense	Exon 16 of 22	ENSP00000310668.5	Q8N1F7-1
	NUP93	ENST00000569842.5	TSL:5	c.1772G>T	p.Gly591Val	missense	Exon 16 of 23	ENSP00000458101.1	H3BVG0
	NUP93	ENST00000923937.1		c.1775G>T	p.Gly592Val	missense	Exon 16 of 22	ENSP00000593996.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250500 AF XY: 0.0000812

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 214 AN: 1459434 Hom.: 0 Cov.: 30 AF XY: 0.000167 AC XY: 121 AN XY: 726012

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000187 AC: 208 AN: 1110260

Other (OTH) AF: 0.0000663 AC: 4 AN: 60292

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Nephrotic syndrome, type 12 (5)
4	-	-	not provided (4)
1	-	-	Nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.90
MPC		1.2
ClinPred		0.77	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.83
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.89		Position offset: -2

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

Other links and lift over

dbSNP: rs145473779; hg19: chr16-56868680;