11-3693259-C-G

Variant names:

• chr11-3693259-C-G
• NM_016320.5:c.4284G>C
• NUP98 p.Ala1428Ala

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP7

The NM_016320.5(NUP98):​c.4284G>C​(p.Ala1428Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A1428A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUP98 NM_016320.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP7: Synonymous conserved (PhyloP=-0.469 with no splicing effect.

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.4284G>C	p.Ala1428Ala	synonymous	Exon 27 of 33	NP_057404.2
	NUP98	NM_001365125.2		c.4377G>C	p.Ala1459Ala	synonymous	Exon 28 of 34	NP_001352054.1
	NUP98	NM_001365126.2		c.4335G>C	p.Ala1445Ala	synonymous	Exon 27 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.4284G>C	p.Ala1428Ala	synonymous	Exon 27 of 33	ENSP00000316032.7	P52948-5
	NUP98	ENST00000429801.5	TSL:1	c.1140G>C	p.Ala380Ala	synonymous	Exon 7 of 13	ENSP00000413146.1	H7C3P6
	NUP98	ENST00000915300.1		c.4428G>C	p.Ala1476Ala	synonymous	Exon 28 of 34	ENSP00000585359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.6
DANN	Benign	0.72
PhyloP100		-0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-3714489;