6-43523209-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 frequency of 0.456 in 170,988 control chromosomes in the GnomAD database, including 19,258 homozygotes. In-silico tool predicts a benign outcome for this variant. 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: 103 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]

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

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

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	NP_065801.1	Q9HAV4
	POLR1C	NM_001318876.2		c.922+2161T>G		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.922+2161T>G		intron	N/A	NP_001350587.1	A0A2R8YEZ4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPO5	ENST00000265351.12	TSL:1 MANE Select	c.*659A>C		3_prime_UTR	Exon 32 of 32	ENSP00000265351.7	Q9HAV4
	POLR1C	ENST00000304004.7	TSL:1	c.922+2161T>G		intron	N/A	ENSP00000307212.3	O15160-2
	XPO5	ENST00000943409.1		c.*659A>C		3_prime_UTR	Exon 32 of 32	ENSP00000613468.1

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70693 AN: 151938 Hom.: 17637 Cov.: 32

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.383 AC: 7256 AN: 18932 Hom.: 1591 Cov.: 0 AF XY: 0.387 AC XY: 3850 AN XY: 9950

African (AFR) AF: 0.629 AC: 220 AN: 350

American (AMR) AF: 0.403 AC: 1258 AN: 3118

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 89 AN: 258

East Asian (EAS) AF: 0.0627 AC: 93 AN: 1484

South Asian (SAS) AF: 0.410 AC: 1083 AN: 2644

European-Finnish (FIN) AF: 0.414 AC: 150 AN: 362

Middle Eastern (MID) AF: 0.550 AC: 11 AN: 20

European-Non Finnish (NFE) AF: 0.411 AC: 4069 AN: 9906

Other (OTH) AF: 0.358 AC: 283 AN: 790

GnomAD4 genome AF: 0.466 AC: 70783 AN: 152056 Hom.: 17667 Cov.: 32 AF XY: 0.465 AC XY: 34516 AN XY: 74306

African (AFR) AF: 0.630 AC: 26140 AN: 41498

American (AMR) AF: 0.427 AC: 6529 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1144 AN: 3464

East Asian (EAS) AF: 0.0654 AC: 339 AN: 5180

South Asian (SAS) AF: 0.398 AC: 1917 AN: 4822

European-Finnish (FIN) AF: 0.444 AC: 4686 AN: 10550

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28536 AN: 67952

Other (OTH) AF: 0.429 AC: 904 AN: 2108

Alfa AF: 0.438 Hom.: 18101

Bravo AF: 0.470

Asia WGS AF: 0.263 AC: 917 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.7
DANN	Benign	0.78
PhyloP100		-0.23
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs11077; hg19: chr6-43490947;