rs1875

chr11-3693259-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_016320.5(NUP98):c.4284G>A(p.Ala1428=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,613,184 control chromosomes in the GnomAD database, including 34,626 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4570 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30056 hom.)
• Consequence: NUP98 NM_016320.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469

Genes affected

NUP98 (HGNC:8068): (nucleoporin 98 and 96 precursor) Nuclear pore complexes (NPCs) regulate the transport of macromolecules between the nucleus and cytoplasm, and are composed of many polypeptide subunits, many of which belong to the nucleoporin family. This gene belongs to the nucleoporin gene family and encodes a 186 kDa precursor protein that undergoes autoproteolytic cleavage to generate a 98 kDa nucleoporin and 96 kDa nucleoporin. The 98 kDa nucleoporin contains a Gly-Leu-Phe-Gly (GLGF) repeat domain and participates in many cellular processes, including nuclear import, nuclear export, mitotic progression, and regulation of gene expression. The 96 kDa nucleoporin is a scaffold component of the NPC. Proteolytic cleavage is important for targeting of the proteins to the NPC. Translocations between this gene and many other partner genes have been observed in different leukemias. Rearrangements typically result in chimeras with the N-terminal GLGF domain of this gene to the C-terminus of the partner gene. Alternative splicing results in multiple transcript variants encoding different isoforms, at least two of which are proteolytically processed. Some variants lack the region that encodes the 96 kDa nucleoporin. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP7: Synonymous conserved (PhyloP=-0.469 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUP98	NM_016320.5	c.4284G>A	p.Ala1428=	synonymous_variant	27/33	ENST00000324932.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUP98	ENST00000324932.12	c.4284G>A	p.Ala1428=	synonymous_variant	27/33	1	NM_016320.5	P4

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34902 AN: 151904 Hom.: 4572 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.205 AC: 51613 AN: 251394 Hom.: 6219 AF XY: 0.210 AC XY: 28598 AN XY: 135880

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.0841

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.306

Gnomad SAS exome AF: 0.298

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.195 AC: 285427 AN: 1461160 Hom.: 30056 Cov.: 32 AF XY: 0.198 AC XY: 143924 AN XY: 726916

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.0870

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.230 AC: 34935 AN: 152024 Hom.: 4570 Cov.: 32 AF XY: 0.233 AC XY: 17290 AN XY: 74300

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.203

Alfa AF: 0.181 Hom.: 3363

Bravo AF: 0.218

Asia WGS AF: 0.290 AC: 1008 AN: 3478

EpiCase AF: 0.176

EpiControl AF: 0.169

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	8.7
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1875; hg19: chr11-3714489; COSMIC: COSV61428691; COSMIC: COSV61428691;