Variant 14-24183148-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024658.4(IPO4):c.2249G>A(p.Arg750Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

IPO4
NM_024658.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.51

Variant links:

Genes affected

IPO4 (HGNC:19426): (importin 4) Predicted to enable nuclear import signal receptor activity and nuclear localization sequence binding activity. Involved in DNA replication-dependent chromatin assembly; DNA replication-independent chromatin assembly; and protein import into nucleus. Located in chromatin. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

IPO4 links:

IPO4 (HGNC:):

IPO4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IPO4	NM_024658.4 linkuse as main transcript	c.2249G>A	p.Arg750Gln	missense_variant	23/30	ENST00000354464.11	NP_078934.3	Q8TEX9-1B3KT38
IPO4	NR_051979.2 linkuse as main transcript	n.2278G>A		non_coding_transcript_exon_variant	23/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
IPO4	ENST00000354464.11 linkuse as main transcript	c.2249G>A	p.Arg750Gln	missense_variant	23/30	1	NM_024658.4	ENSP00000346453.6	Q8TEX9-1
ENSG00000259522	ENST00000561419.1 linkuse as main transcript	n.*2876G>A		non_coding_transcript_exon_variant	24/31	2		ENSP00000454374.1	H3BMG7
ENSG00000259522	ENST00000561419.1 linkuse as main transcript	n.*2876G>A		3_prime_UTR_variant	24/31	2		ENSP00000454374.1	H3BMG7

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000129

AC:

AN:

248810

Hom.:

AF XY:

0.0000962

AC XY:

AN XY:

135128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000501

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000103

AC:

150

AN:

1460442

Hom.:

Cov.:

AF XY:

0.0000964

AC XY:

AN XY:

726254

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.000104

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.000112

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000240

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.2249G>A (p.R750Q) alteration is located in exon 23 (coding exon 23) of the IPO4 gene. This alteration results from a G to A substitution at nucleotide position 2249, causing the arginine (R) at amino acid position 750 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.0051

FATHMM_MKL

Uncertain

0.78

M_CAP

Benign

0.027

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.41

PROVEAN

Benign

0.38

REVEL

Benign

0.079

Sift

Benign

0.26

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.18

MVP

0.63

MPC

0.26

ClinPred

0.047

GERP RS

5.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.4

Varity_R

0.070

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -23

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