11-3676364-C-G

Variant names:

• chr11-3676364-C-G
• rs143602983
• NM_016320.5:c.5198G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016320.5(NUP98):​c.5198G>C​(p.Arg1733Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1733H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NUP98 NM_016320.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016320.5. 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
	NUP98	NM_016320.5	MANE Select	c.5198G>C	p.Arg1733Pro	missense	Exon 33 of 33	NP_057404.2
	NUP98	NM_001365125.2		c.5291G>C	p.Arg1764Pro	missense	Exon 34 of 34	NP_001352054.1
	NUP98	NM_001365126.2		c.5249G>C	p.Arg1750Pro	missense	Exon 33 of 33	NP_001352055.1	P52948-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUP98	ENST00000324932.12	TSL:1 MANE Select	c.5198G>C	p.Arg1733Pro	missense	Exon 33 of 33	ENSP00000316032.7	P52948-5
	NUP98	ENST00000429801.5	TSL:1	c.2054G>C	p.Arg685Pro	missense	Exon 13 of 13	ENSP00000413146.1	H7C3P6
	NUP98	ENST00000915300.1		c.5342G>C	p.Arg1781Pro	missense	Exon 34 of 34	ENSP00000585359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727134

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111882

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.87	P
Vest4		0.72
MutPred		0.44		Loss of MoRF binding (P = 0.0019)
MVP		0.40
MPC		0.84
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.39
gMVP		0.80
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143602983; hg19: chr11-3697594;