14-24180480-T-C

Position:

• chr14-24180480-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024658.4(IPO4):​c.3208A>G​(p.Lys1070Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: IPO4 NM_024658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

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 (HGNC:):

REC8 (HGNC:16879): (REC8 meiotic recombination protein) This gene encodes a member of the kleisin family of SMC (structural maintenance of chromosome) protein partners. The protein localizes to the axial elements of chromosomes during meiosis in both oocytes and spermatocytes. In the mouse, the homologous protein is a key component of the meiotic cohesion complex, which regulates sister chromatid cohesion and recombination between homologous chromosomes. Multiple alternatively spliced variants, encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13121113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IPO4	NM_024658.4	c.3208A>G	p.Lys1070Glu	missense_variant	30/30	ENST00000354464.11	NP_078934.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IPO4	ENST00000354464.11	c.3208A>G	p.Lys1070Glu	missense_variant	30/30	1	NM_024658.4	ENSP00000346453.6
ENSG00000259522	ENST00000561419.1	n.*3835A>G		non_coding_transcript_exon_variant	31/31	2		ENSP00000454374.1
ENSG00000259522	ENST00000561419.1	n.*3835A>G		3_prime_UTR_variant	31/31	2		ENSP00000454374.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461386 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jun 23, 2023

The c.3208A>G (p.K1070E) alteration is located in exon 30 (coding exon 30) of the IPO4 gene. This alteration results from a A to G substitution at nucleotide position 3208, causing the lysine (K) at amino acid position 1070 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	0.10
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.075
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.094
Sift	Benign	0.68	T
Sift4G	Benign	0.077	T
Polyphen		0.13	B
Vest4		0.35
MutPred		0.46		Loss of ubiquitination at K1070 (P = 0.0161);
MVP		0.33
MPC		0.32
ClinPred		0.81	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs2039114140; hg19: chr14-24649686;