NM_003400.4:c.888+9A>G

Variant names:

• chr2-61496870-T-C
• rs140857799
• NM_003400.4:c.888+9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003400.4(XPO1):​c.888+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,577,470 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (15 hom.)
• Consequence: XPO1 NM_003400.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.313
• 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-61496870-T-C is Benign according to our data. Variant chr2-61496870-T-C is described in ClinVar as Benign. ClinVar VariationId is 775721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00767 (1168/152366) while in subpopulation AFR AF = 0.0269 (1118/41586). AF 95% confidence interval is 0.0256. There are 20 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1168 AD gene.

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.888+9A>G		intron	N/A	NP_003391.1	O14980
	XPO1	NM_001410799.1		c.888+9A>G		intron	N/A	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.888+9A>G		intron	N/A	ENSP00000384863.2	O14980
	XPO1	ENST00000406957.5	TSL:1	c.888+9A>G		intron	N/A	ENSP00000385559.1	O14980
	XPO1	ENST00000404992.6	TSL:2	c.888+9A>G		intron	N/A	ENSP00000385942.2	O14980

Frequencies

GnomAD3 genomes AF: 0.00767 AC: 1168 AN: 152248 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00193 AC: 424 AN: 219172 AF XY: 0.00132

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.000922

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000386

Gnomad OTH exome AF: 0.000757

GnomAD4 exome AF: 0.000735 AC: 1048 AN: 1425104 Hom.: 15 Cov.: 30 AF XY: 0.000602 AC XY: 426 AN XY: 707730

African (AFR) AF: 0.0286 AC: 902 AN: 31532

American (AMR) AF: 0.00108 AC: 38 AN: 35060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24680

East Asian (EAS) AF: 0.00 AC: 0 AN: 38540

South Asian (SAS) AF: 0.0000503 AC: 4 AN: 79590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52800

Middle Eastern (MID) AF: 0.00124 AC: 7 AN: 5636

European-Non Finnish (NFE) AF: 0.0000155 AC: 17 AN: 1098278

Other (OTH) AF: 0.00136 AC: 80 AN: 58988

GnomAD4 genome AF: 0.00767 AC: 1168 AN: 152366 Hom.: 20 Cov.: 32 AF XY: 0.00742 AC XY: 553 AN XY: 74514

African (AFR) AF: 0.0269 AC: 1118 AN: 41586

American (AMR) AF: 0.00209 AC: 32 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00326 Hom.: 4

Bravo AF: 0.00855

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.42
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism

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

dbSNP: rs140857799; hg19: chr2-61724005;