chr11-3683214-C-T

Position:

chr11-3683214-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016320.5(NUP98):c.4904G>A(p.Arg1635Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,110 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

NUP98
NM_016320.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.518

Variant links:

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]

NUP98 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032928288).

BP6

Variant 11-3683214-C-T is Benign according to our data. Variant chr11-3683214-C-T is described in ClinVar as [Benign]. Clinvar id is 718546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00539 (821/152236) while in subpopulation AFR AF= 0.0178 (741/41546). AF 95% confidence interval is 0.0168. There are 4 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 821 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUP98	NM_016320.5 linkuse as main transcript	c.4904G>A	p.Arg1635Gln	missense_variant	30/33	ENST00000324932.12	NP_057404.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUP98	ENST00000324932.12 linkuse as main transcript	c.4904G>A	p.Arg1635Gln	missense_variant	30/33	1	NM_016320.5	ENSP00000316032	P4	P52948-5

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

819

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00153

AC:

384

AN:

251344

Hom.:

AF XY:

0.00121

AC XY:

165

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.0177

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000563

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.00117

AC:

1707

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

801

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0182

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000827

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00539

AC:

821

AN:

152236

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

407

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0178

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00140

Hom.:

Bravo

AF:

0.00603

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.052

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.80

.;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.32

N;.;N

REVEL

Benign

0.024

Sift

Benign

0.54

T;.;T

Sift4G

Benign

0.64

T;T;T

Polyphen

0.089

B;.;B

Vest4

0.22

MVP

0.20

MPC

0.22

ClinPred

0.0097

GERP RS

0.10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over