6-43524840-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020750.3(XPO5):c.3303C>T(p.Tyr1101=) 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. In-silico tool predicts a benign outcome for this variant. 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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• 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/exons	MANE	UniProt
XPO5	NM_020750.3	c.3303C>T	p.Tyr1101=	synonymous_variant	30/32	ENST00000265351.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPO5	ENST00000265351.12	c.3303C>T	p.Tyr1101=	synonymous_variant	30/32	1	NM_020750.3	P1

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

GnomAD3 exomes AF: 0.300 AC: 74602 AN: 248854 Hom.: 12538 AF XY: 0.297 AC XY: 40112 AN XY: 135022

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 SAS exome AF: 0.283

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

Gnomad4 AMR exome AF: 0.297

Gnomad4 ASJ exome AF: 0.290

Gnomad4 EAS exome AF: 0.615

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.291

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

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.622

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.281

Alfa AF: 0.269 Hom.: 13239

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

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

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;