14-24182839-C-A

Position:

• chr14-24182839-C-A

Variant summary

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

The NM_024658.4(IPO4):​c.2425G>T​(p.Ala809Ser) 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. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IPO4 NM_024658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.485

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]

ENSG00000259522 (HGNC:):

ACMG classification

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	c.2425G>T	p.Ala809Ser	missense_variant	24/30	ENST00000354464.11	NP_078934.3
IPO4	NR_051979.2	n.2454G>T		non_coding_transcript_exon_variant	24/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IPO4	ENST00000354464.11	c.2425G>T	p.Ala809Ser	missense_variant	24/30	1	NM_024658.4	ENSP00000346453.6
ENSG00000259522	ENST00000561419.1	n.*3052G>T		non_coding_transcript_exon_variant	25/31	2		ENSP00000454374.1
ENSG00000259522	ENST00000561419.1	n.*3052G>T		3_prime_UTR_variant	25/31	2		ENSP00000454374.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Aug 05, 2024

The c.2425G>T (p.A809S) alteration is located in exon 24 (coding exon 24) of the IPO4 gene. This alteration results from a G to T substitution at nucleotide position 2425, causing the alanine (A) at amino acid position 809 to be replaced by a serine (S). 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	0.094
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0040
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Benign	0.23	T
Sift4G	Benign	0.088	T
Polyphen		0.59	P
Vest4		0.29
MutPred		0.35		Gain of phosphorylation at A809 (P = 0.0203);
MVP		0.59
MPC		0.26
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.14
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -9

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: chr14-24652045;