rs138909849

Variant names:

• chr16-56833407-G-A
• rs138909849
• NM_014669.5:c.1537+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56833407-G-A
• chr16-56833407-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_014669.5(NUP93):​c.1537+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000395 in 1,518,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: NUP93 NM_014669.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.94
• Publications: 5 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07804878 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of 30, new splice context is: aatGTaacc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 16-56833407-G-A is Pathogenic according to our data. Variant chr16-56833407-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 224967.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP93	NM_014669.5	MANE Select	c.1537+1G>A		splice_donor intron	N/A	NP_055484.3
	NUP93	NM_001242795.2		c.1168+1G>A		splice_donor intron	N/A	NP_001229724.1
	NUP93	NM_001242796.2		c.1168+1G>A		splice_donor intron	N/A	NP_001229725.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP93	ENST00000308159.10	TSL:1 MANE Select	c.1537+1G>A		splice_donor intron	N/A	ENSP00000310668.5
	NUP93	ENST00000569842.5	TSL:5	c.1537+1G>A		splice_donor intron	N/A	ENSP00000458101.1
	NUP93	ENST00000542526.5	TSL:2	c.1168+1G>A		splice_donor intron	N/A	ENSP00000440235.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome AF: 0.00000293 AC: 4 AN: 1366760 Hom.: 0 Cov.: 31 AF XY: 0.00000297 AC XY: 2 AN XY: 674374

African (AFR) AF: 0.00 AC: 0 AN: 27812

American (AMR) AF: 0.00 AC: 0 AN: 25424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22684

East Asian (EAS) AF: 0.00 AC: 0 AN: 34210

South Asian (SAS) AF: 0.00 AC: 0 AN: 70414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4804

European-Non Finnish (NFE) AF: 0.00000373 AC: 4 AN: 1072782

Other (OTH) AF: 0.00 AC: 0 AN: 56238

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000399 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Nephrotic syndrome, type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.9
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 3
DS_DL_spliceai		0.98		Position offset: -1

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

Other links and lift over

dbSNP: rs138909849; hg19: chr16-56867319; COSMIC: COSV57431579; COSMIC: COSV57431579;