2-61488243-A-C

Variant names:

• chr2-61488243-A-C
• rs762581181
• NM_003400.4:c.2235T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003400.4(XPO1):​c.2235T>G​(p.Ile745Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: XPO1 NM_003400.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

XPO1 (HGNC:12825): (exportin 1) This cell-cycle-regulated gene encodes a protein that mediates leucine-rich nuclear export signal (NES)-dependent protein transport. The protein specifically inhibits the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MPAK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPO1	NM_003400.4	c.2235T>G	p.Ile745Met	missense_variant	Exon 19 of 25	ENST00000401558.7	NP_003391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPO1	ENST00000401558.7	c.2235T>G	p.Ile745Met	missense_variant	Exon 19 of 25	1	NM_003400.4	ENSP00000384863.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251262 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461648 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727116

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2235T>G (p.I745M) alteration is located in exon 19 (coding exon 18) of the XPO1 gene. This alteration results from a T to G substitution at nucleotide position 2235, causing the isoleucine (I) at amino acid position 745 to be replaced by a methionine (M). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.71
MutPred		0.78		Gain of disorder (P = 0.0315);Gain of disorder (P = 0.0315);Gain of disorder (P = 0.0315);
MVP		0.80
MPC		2.6
ClinPred		0.96	D
GERP RS		-0.63
Varity_R		0.88
gMVP		0.84

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

Other links and lift over

dbSNP: rs762581181; hg19: chr2-61715378; COSMIC: COSV101294137; COSMIC: COSV101294137;