rs61762965

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_020750.3(XPO5):c.1157G>A(p.Arg386His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,611,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

XPO5
NM_020750.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.864

Publications

1 publications found

Variant links:

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]

XPO5 links:

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]

POLR1C Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 11
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Treacher Collins syndrome 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
Treacher-Collins syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006357193).

BP6

Variant 6-43560242-C-T is Benign according to our data. Variant chr6-43560242-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2075317.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 119 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020750.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
XPO5	NM_020750.3	MANE Select	c.1157G>A	p.Arg386His	missense	Exon 11 of 32	NP_065801.1
XPO5	NR_144392.2		n.1331G>A		non_coding_transcript_exon	Exon 11 of 33
POLR1C	NM_001363658.2		c.*43-1158C>T		intron	N/A	NP_001350587.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
XPO5	ENST00000265351.12	TSL:1 MANE Select	c.1157G>A	p.Arg386His	missense	Exon 11 of 32	ENSP00000265351.7
XPO5	ENST00000496341.6	TSL:5	n.233G>A		non_coding_transcript_exon	Exon 3 of 8	ENSP00000424196.1
POLR1C	ENST00000646433.1		c.923-1158C>T		intron	N/A	ENSP00000494368.1

Frequencies

GnomAD3 genomes

AF:

0.000784

AC:

119

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00276

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

246314

AF XY:

0.000157

show subpopulations

Gnomad AFR exome

AF:

0.00231

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000806

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000959

AC:

140

AN:

1460060

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

726160

show subpopulations

African (AFR)

AF:

0.00269

AC:

AN:

33470

American (AMR)

AF:

0.000112

AC:

AN:

44456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

85862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111106

Other (OTH)

AF:

0.000215

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000783

AC:

119

AN:

151918

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.00275

AC:

114

AN:

41390

American (AMR)

AF:

0.000262

AC:

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000332

Hom.:

Bravo

AF:

0.000824

ESP6500AA

AF:

0.00190

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000290

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

XPO5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.076

Eigen_PC

Benign

0.051

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.84

M_CAP

Benign

0.021

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

PhyloP100

0.86

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.1

REVEL

Benign

0.18

Sift

Uncertain

0.011

Sift4G

Benign

0.22

Polyphen

0.48

Vest4

0.061

MVP

0.36

MPC

0.48

ClinPred

0.062

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.20

Mutation Taster

=71/29

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over