chr2-61495586-G-A

Position:

• chr2-61495586-G-A

Variant summary

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

The NM_003400.4(XPO1):​c.916C>T​(p.Leu306Phe) 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. 13/20 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)
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106090575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPO1	NM_003400.4	c.916C>T	p.Leu306Phe	missense_variant	11/25	ENST00000401558.7	NP_003391.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPO1	ENST00000401558.7	c.916C>T	p.Leu306Phe	missense_variant	11/25	1	NM_003400.4	ENSP00000384863.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 02, 2023

The c.916C>T (p.L306F) alteration is located in exon 11 (coding exon 10) of the XPO1 gene. This alteration results from a C to T substitution at nucleotide position 916, causing the leucine (L) at amino acid position 306 to be replaced by a phenylalanine (F). 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	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	.;.;D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.056
Sift	Benign	0.056	T;T;T
Sift4G	Benign	0.068	T;T;T
Polyphen		0.20	B;B;B
Vest4		0.15
MutPred		0.32		Gain of disorder (P = 0.2449);Gain of disorder (P = 0.2449);Gain of disorder (P = 0.2449);
MVP		0.18
MPC		1.4
ClinPred		0.57	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-61722721;