rs2257082

Variant names:

• chr6-43524840-G-A
• rs2257082
• NM_020750.3:c.3303C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_020750.3(XPO5):​c.3303C>T​(p.Tyr1101Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,612,466 control chromosomes in the GnomAD database, including 67,186 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5882 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61304 hom.)
• Consequence: XPO5 NM_020750.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.280

Genes affected

XPO5 (HGNC:17675): (exportin 5) This gene encodes a member of the karyopherin family that is required for the transport of small RNAs and double-stranded RNA-binding proteins from the nucleus to the cytoplasm. The encoded protein translocates cargo through the nuclear pore complex in a RanGTP-dependent process. [provided by RefSeq, Aug 2011]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 6-43524840-G-A is Benign according to our data. Variant chr6-43524840-G-A is described in ClinVar as [Benign]. Clinvar id is 1262421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPO5	NM_020750.3	c.3303C>T	p.Tyr1101Tyr	synonymous_variant	Exon 30 of 32	ENST00000265351.12	NP_065801.1
POLR1C	NM_001318876.2	c.922+3792G>A		intron_variant	Intron 8 of 8		NP_001305805.1
POLR1C	NM_001363658.2	c.922+3792G>A		intron_variant	Intron 8 of 9		NP_001350587.1
XPO5	NR_144392.2	n.3615C>T		non_coding_transcript_exon_variant	Exon 31 of 33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPO5	ENST00000265351.12	c.3303C>T	p.Tyr1101Tyr	synonymous_variant	Exon 30 of 32	1	NM_020750.3	ENSP00000265351.7

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40080 AN: 151340 Hom.: 5873 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.272

GnomAD2 exomes AF: 0.300 AC: 74602 AN: 248854 AF XY: 0.297

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.282 AC: 412288 AN: 1461014 Hom.: 61304 Cov.: 39 AF XY: 0.282 AC XY: 204789 AN XY: 726822

Gnomad4 AFR exome AF: 0.167 AC: 5566 AN: 33348

Gnomad4 AMR exome AF: 0.297 AC: 13290 AN: 44706

Gnomad4 ASJ exome AF: 0.290 AC: 7572 AN: 26134

Gnomad4 EAS exome AF: 0.615 AC: 24404 AN: 39700

Gnomad4 SAS exome AF: 0.279 AC: 24077 AN: 86232

Gnomad4 FIN exome AF: 0.329 AC: 17579 AN: 53360

Gnomad4 NFE exome AF: 0.271 AC: 301085 AN: 1111834

Gnomad4 Remaining exome AF: 0.291 AC: 17524 AN: 60318

GnomAD4 genome AF: 0.265 AC: 40108 AN: 151452 Hom.: 5882 Cov.: 32 AF XY: 0.269 AC XY: 19939 AN XY: 74060

Gnomad4 AFR AF: 0.178 AC: 0.177843 AN: 0.177843

Gnomad4 AMR AF: 0.278 AC: 0.27753 AN: 0.27753

Gnomad4 ASJ AF: 0.288 AC: 0.287608 AN: 0.287608

Gnomad4 EAS AF: 0.622 AC: 0.621564 AN: 0.621564

Gnomad4 SAS AF: 0.282 AC: 0.282482 AN: 0.282482

Gnomad4 FIN AF: 0.328 AC: 0.32771 AN: 0.32771

Gnomad4 NFE AF: 0.274 AC: 0.273826 AN: 0.273826

Gnomad4 OTH AF: 0.281 AC: 0.280894 AN: 0.280894

Alfa AF: 0.268 Hom.: 26021

Bravo AF: 0.257

Asia WGS AF: 0.456 AC: 1588 AN: 3478

EpiCase AF: 0.264

EpiControl AF: 0.254

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.9
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs2257082; hg19: chr6-43492578; COSMIC: COSV54830091; COSMIC: COSV54830091;