14-24182026-G-C

Position:

• chr14-24182026-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000354464.11(IPO4):​c.2736C>G​(p.Asp912Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IPO4 ENST00000354464.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.773

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31361753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IPO4	NM_024658.4	c.2736C>G	p.Asp912Glu	missense_variant	26/30	ENST00000354464.11	NP_078934.3
IPO4	NR_051979.2	n.2785C>G		non_coding_transcript_exon_variant	26/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IPO4	ENST00000354464.11	c.2736C>G	p.Asp912Glu	missense_variant	26/30	1	NM_024658.4	ENSP00000346453	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.2736C>G (p.D912E) alteration is located in exon 26 (coding exon 26) of the IPO4 gene. This alteration results from a C to G substitution at nucleotide position 2736, causing the aspartic acid (D) at amino acid position 912 to be replaced by a glutamic acid (E). 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	0.32
BayesDel_addAF	Benign	0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Benign	0.060	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.64	P
Vest4		0.37
MutPred		0.69		Gain of disorder (P = 0.1038);
MVP		0.64
MPC		0.58
ClinPred		0.82	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.30
gMVP		0.18

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24651232;