chr2-61485919-A-T

Variant names:

• chr2-61485919-A-T
• NM_003400.4:c.2357T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003400.4(XPO1):​c.2357T>A​(p.Ile786Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.22
• Publications: 0 publications found

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]

USP34-DT (HGNC:55262): (USP34 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 6.0107 (above the threshold of 3.09). Trascript score misZ: 7.9387 (above the threshold of 3.09).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003400.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPO1	NM_003400.4	MANE Select	c.2357T>A	p.Ile786Asn	missense	Exon 20 of 25	NP_003391.1	O14980
	XPO1	NM_001410799.1		c.2222T>A	p.Ile741Asn	missense	Exon 19 of 24	NP_001397728.1	A0A7I2V2Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPO1	ENST00000401558.7	TSL:1 MANE Select	c.2357T>A	p.Ile786Asn	missense	Exon 20 of 25	ENSP00000384863.2	O14980
	XPO1	ENST00000406957.5	TSL:1	c.2357T>A	p.Ile786Asn	missense	Exon 21 of 26	ENSP00000385559.1	O14980
	XPO1	ENST00000404992.6	TSL:2	c.2357T>A	p.Ile786Asn	missense	Exon 20 of 25	ENSP00000385942.2	O14980

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.34
Sift	Benign	0.34	T
Sift4G	Benign	0.34	T
Polyphen		0.87	P
Vest4		0.79
MutPred		0.55		Gain of disorder (P = 0.0782)
MVP		0.68
MPC		2.4
ClinPred		0.73	D
GERP RS		6.2
Varity_R		0.52
gMVP		0.86
Mutation Taster		=24/76	disease causing

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

Other links and lift over

hg19: chr2-61713054;