NM_020750.3:c.*659A>C

Variant names:

• chr6-43523209-T-G
• rs11077
• NM_020750.3:c.*659A>C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_020750.3(XPO5):c.*659A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.456 (AC=78,039) in the gnomAD database across 170,988 control chromosomes, including 19,258 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.624. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.47 (17667 hom., cov: 32)
  • Exomes 𝑓: 0.38 (1591 hom.)
• Consequence: XPO5 NM_020750.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.233
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• nephrotic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

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):

• POLR1C-related disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• leukodystrophy, hypomyelinating, 11

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Treacher Collins syndrome 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• Treacher-Collins syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6235 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	XPO5 NM_020750.3	MANE Select	c.*659A>C	3_prime_UTR	Exon 32 of 32	Prot: NP_065801.1 UniProt:
	POLR1C NM_001318876.2		c.922+2161T>G	intron	Intron 8 of 8	Prot: NP_001305805.1 UniProt:
	POLR1C NM_001363658.2		c.922+2161T>G	intron	Intron 8 of 9	Prot: NP_001350587.1 UniProt:

XPO5 NM_020750.3

MANE Select

HGVSc / HGVSpc.*659A>C

Exon rankExon 32 of 32

3_prime_UTR

Prot: NP_065801.1UniProt: Q9HAV4

POLR1C NM_001318876.2

HGVSc / HGVSpc.922+2161T>G

Exon rankIntron 8 of 8

intron

Prot: NP_001305805.1UniProt: O15160-2

POLR1C NM_001363658.2

HGVSc / HGVSpc.922+2161T>G

Exon rankIntron 8 of 9

intron

Prot: NP_001350587.1UniProt: A0A2R8YEZ4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	XPO5 ENST00000265351.12	TSL:1MANE Select	c.*659A>C	3_prime_UTR	Exon 32 of 32	Prot: ENSP00000265351.7 UniProt:
	POLR1C ENST00000304004.7	TSL:1	c.922+2161T>G	intron	Intron 8 of 8	Prot: ENSP00000307212.3 UniProt:
	XPO5 ENST00000943409.1		c.*659A>C	3_prime_UTR	Exon 32 of 32	Prot: ENSP00000613468.1 UniProt:

XPO5 ENST00000265351.12

TSL:1MANE Select

HGVSc / HGVSpc.*659A>C

Exon rankExon 32 of 32

3_prime_UTR

Prot: ENSP00000265351.7UniProt: Q9HAV4

POLR1C ENST00000304004.7

TSL:1

HGVSc / HGVSpc.922+2161T>G

Exon rankIntron 8 of 8

intron

Prot: ENSP00000307212.3UniProt: O15160-2

XPO5 ENST00000943409.1

HGVSc / HGVSpc.*659A>C

Exon rankExon 32 of 32

3_prime_UTR

Prot: ENSP00000613468.1UniProt: A0ACI8U9B7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.465	AC:70693	Hom:17637	AN:151938	Cov:32
GnomAD4 exome	AF: 0.383	AC:7256	Hom:1591	AN:18932	Cov:0
GnomAD4 genome	AF: 0.466	AC:70783	Hom:17667	AN:152056	Cov:32
TOPMed (Bravo)	AF: 0.470	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.441	AC:92246	Hom:20886	AN:209136	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.470	AC:1100	Hom:291	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0738	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.407	AC:122	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.263	AC:917	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0780	AC:564	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.386	AC:68	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0684	AC:8396	Hom:287	AN:122670	Cov:
Turkish Variome	AF: 0.396	AC:612	Hom:113	AN:1546	Cov:
UK10K	AF: 0.425	AC:3216	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0670	AC:600	Hom:23	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.255	6020	23630	0.129	3947	30642

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	3.1
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.7
DANN	Benign	0.78
GPN-Star LLR	N/A	6.8
GPN-Star score	N/A	2.0
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.23

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs11077;

hg19: chr6-43490947;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar