rs1875

Variant names:

• chr11-3693259-C-T
• rs1875
• NM_016320.5:c.4284G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP7 BA1

The NM_016320.5(NUP98):​c.4284G>A​(p.Ala1428Ala) 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. 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
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• 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 rank	MANE	Protein	UniProt
NUP98	NM_016320.5	c.4284G>A	p.Ala1428Ala	synonymous_variant	Exon 27 of 33	ENST00000324932.12	NP_057404.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NUP98	ENST00000324932.12	c.4284G>A	p.Ala1428Ala	synonymous_variant	Exon 27 of 33	1	NM_016320.5	ENSP00000316032.7

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

GnomAD2 exomes AF: 0.205 AC: 51613 AN: 251394 AF XY: 0.210

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 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

African (AFR) AF: 0.352 AC: 11775 AN: 33460

American (AMR) AF: 0.0870 AC: 3889 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3433 AN: 26132

East Asian (EAS) AF: 0.312 AC: 12373 AN: 39692

South Asian (SAS) AF: 0.296 AC: 25557 AN: 86236

European-Finnish (FIN) AF: 0.269 AC: 14385 AN: 53406

Middle Eastern (MID) AF: 0.176 AC: 1013 AN: 5766

European-Non Finnish (NFE) AF: 0.181 AC: 200835 AN: 1111384

Other (OTH) AF: 0.202 AC: 12167 AN: 60366

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

African (AFR) AF: 0.332 AC: 13772 AN: 41438

American (AMR) AF: 0.116 AC: 1774 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3468

East Asian (EAS) AF: 0.309 AC: 1594 AN: 5160

South Asian (SAS) AF: 0.295 AC: 1423 AN: 4820

European-Finnish (FIN) AF: 0.292 AC: 3086 AN: 10552

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12266 AN: 67988

Other (OTH) AF: 0.203 AC: 427 AN: 2108

Alfa AF: 0.185 Hom.: 4265

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
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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