6-43524352-CAAAAAAAAA-CAAAAAAA

Variant names:

• chr6-43524352-CAA-C
• rs368583529
• NM_020750.3:c.3477+117_3477+118delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_020750.3(XPO5):​c.3477+117_3477+118delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0544 in 1,024,624 control chromosomes in the GnomAD database, including 22 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (20 hom., cov: 26)
  • Exomes 𝑓: 0.058 (2 hom.)
• Consequence: XPO5 NM_020750.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 0 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0166 (1578/94892) while in subpopulation AFR AF = 0.0473 (1397/29514). AF 95% confidence interval is 0.0453. There are 20 homozygotes in GnomAd4. There are 720 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1578 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XPO5	NM_020750.3	MANE Select	c.3477+117_3477+118delTT		intron	N/A	NP_065801.1	Q9HAV4
	POLR1C	NM_001318876.2		c.922+3322_922+3323delAA		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.922+3322_922+3323delAA		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.3477+117_3477+118delTT		intron	N/A	ENSP00000265351.7	Q9HAV4
	POLR1C	ENST00000304004.7	TSL:1	c.922+3305_922+3306delAA		intron	N/A	ENSP00000307212.3	O15160-2
	XPO5	ENST00000943409.1		c.3474+117_3474+118delTT		intron	N/A	ENSP00000613468.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 1574 AN: 94894 Hom.: 20 Cov.: 26

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.000431

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00513

Gnomad MID AF: 0.0244

Gnomad NFE AF: 0.000781

Gnomad OTH AF: 0.0113

GnomAD4 exome AF: 0.0583 AC: 54157 AN: 929732 Hom.: 2 AF XY: 0.0590 AC XY: 26962 AN XY: 456660

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.130 AC: 2691 AN: 20662

American (AMR) AF: 0.0784 AC: 1211 AN: 15442

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 980 AN: 15104

East Asian (EAS) AF: 0.0577 AC: 1633 AN: 28320

South Asian (SAS) AF: 0.0810 AC: 3818 AN: 47160

European-Finnish (FIN) AF: 0.0623 AC: 1874 AN: 30062

Middle Eastern (MID) AF: 0.0642 AC: 174 AN: 2712

European-Non Finnish (NFE) AF: 0.0538 AC: 39267 AN: 730324

Other (OTH) AF: 0.0628 AC: 2509 AN: 39946

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0166 AC: 1578 AN: 94892 Hom.: 20 Cov.: 26 AF XY: 0.0161 AC XY: 720 AN XY: 44752

African (AFR) AF: 0.0473 AC: 1397 AN: 29514

American (AMR) AF: 0.0120 AC: 102 AN: 8466

Ashkenazi Jewish (ASJ) AF: 0.000431 AC: 1 AN: 2318

East Asian (EAS) AF: 0.00 AC: 0 AN: 2930

South Asian (SAS) AF: 0.00104 AC: 3 AN: 2888

European-Finnish (FIN) AF: 0.00513 AC: 24 AN: 4676

Middle Eastern (MID) AF: 0.0267 AC: 4 AN: 150

European-Non Finnish (NFE) AF: 0.000781 AC: 33 AN: 42236

Other (OTH) AF: 0.0112 AC: 14 AN: 1248

Alfa AF: 0.00 Hom.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.075
Mutation Taster		=100/0	polymorphism

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: rs368583529; hg19: chr6-43492090;