Genetic Variant NM_014669.5:c.1537+1G>T (chr16-56833407-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_014669.5(NUP93):c.1537+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,366,760 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

NUP93
NM_014669.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.94

Publications

0 publications found

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 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

NUP93 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NUP93	NM_014669.5 link	c.1537+1G>T	splice_donor_variant, intron_variant	Intron 13 of 21	ENST00000308159.10	NP_055484.3	Q8N1F7-1
NUP93	NM_001242795.2 link	c.1168+1G>T	splice_donor_variant, intron_variant	Intron 11 of 19		NP_001229724.1	Q8N1F7-2
NUP93	NM_001242796.2 link	c.1168+1G>T	splice_donor_variant, intron_variant	Intron 11 of 19		NP_001229725.1	Q8N1F7-2
NUP93	XM_005256263.4 link	c.1537+1G>T	splice_donor_variant, intron_variant	Intron 13 of 21		XP_005256320.1	Q8N1F7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP93	ENST00000308159.10 link	c.1537+1G>T		splice_donor_variant, intron_variant	Intron 13 of 21	1	NM_014669.5	ENSP00000310668.5		Q8N1F7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.32e-7

AC:

AN:

1366760

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

674374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27812

American (AMR)

AF:

0.00

AC:

AN:

25424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22684

East Asian (EAS)

AF:

0.00

AC:

AN:

34210

South Asian (SAS)

AF:

0.00

AC:

AN:

70414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4804

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072782

Other (OTH)

AF:

0.00

AC:

AN:

56238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.3

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

PhyloP100

9.9

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: 3

DS_DL_spliceai

0.99

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over