6-43567281-C-T

Position:

• chr6-43567281-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020750.3(XPO5):​c.722G>A​(p.Ser241Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.071 in 1,613,612 control chromosomes in the GnomAD database, including 4,424 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.056 (344 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4080 hom.)
• Consequence: XPO5 NM_020750.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.221

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]

XPO5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002454251).
• BP6: Variant 6-43567281-C-T is Benign according to our data. Variant chr6-43567281-C-T is described in ClinVar as [Benign]. Clinvar id is 1282374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPO5	NM_020750.3	c.722G>A	p.Ser241Asn	missense_variant	7/32	ENST00000265351.12	NP_065801.1
POLR1C	NM_001318876.2	c.945+38010C>T		intron_variant			NP_001305805.1
XPO5	NR_144392.2	n.896G>A		non_coding_transcript_exon_variant	7/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPO5	ENST00000265351.12	c.722G>A	p.Ser241Asn	missense_variant	7/32	1	NM_020750.3	ENSP00000265351.7

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8517 AN: 152088 Hom.: 344 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.000960

Gnomad SAS AF: 0.0543

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0765

Gnomad OTH AF: 0.0535

GnomAD3 exomes AF: 0.0626 AC: 15582 AN: 248974 Hom.: 572 AF XY: 0.0637 AC XY: 8609 AN XY: 135090

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.0582

Gnomad ASJ exome AF: 0.0562

Gnomad EAS exome AF: 0.000389

Gnomad SAS exome AF: 0.0574

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.0744

Gnomad OTH exome AF: 0.0720

GnomAD4 exome AF: 0.0726 AC: 106097 AN: 1461406 Hom.: 4080 Cov.: 31 AF XY: 0.0722 AC XY: 52513 AN XY: 726980

Gnomad4 AFR exome AF: 0.00992

Gnomad4 AMR exome AF: 0.0594

Gnomad4 ASJ exome AF: 0.0586

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0576

Gnomad4 FIN exome AF: 0.0953

Gnomad4 NFE exome AF: 0.0786

Gnomad4 OTH exome AF: 0.0639

GnomAD4 genome AF: 0.0560 AC: 8517 AN: 152206 Hom.: 344 Cov.: 32 AF XY: 0.0572 AC XY: 4259 AN XY: 74414

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0573

Gnomad4 ASJ AF: 0.0556

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.0765

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0692 Hom.: 612

Bravo AF: 0.0506

TwinsUK AF: 0.0796 AC: 295

ALSPAC AF: 0.0758 AC: 292

ESP6500AA AF: 0.0132 AC: 51

ESP6500EA AF: 0.0719 AC: 594

ExAC AF: 0.0613 AC: 7407

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.0719

EpiControl AF: 0.0733

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	Labcorp Genetics (formerly Invitae), Labcorp	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
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.56
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.46	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.11
Sift	Benign	0.82	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.080
MPC		0.35
ClinPred		0.0011	T
GERP RS		-1.9
Varity_R		0.050
gMVP		0.13

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: rs34324334; hg19: chr6-43535018; COSMIC: COSV54828726; COSMIC: COSV54828726;