6-43524352-CAAAAAAAAA-CAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_020750.3(XPO5):​c.3477+117_3477+118dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,064,304 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0031 (0 hom.)
• Consequence: XPO5 NM_020750.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.387
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 24 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+118dupTT		intron	N/A	NP_065801.1	Q9HAV4
	POLR1C	NM_001318876.2		c.922+3322_922+3323dupAA		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.922+3322_922+3323dupAA		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+118_3477+119insTT		intron	N/A	ENSP00000265351.7	Q9HAV4
	POLR1C	ENST00000304004.7	TSL:1	c.922+3304_922+3305insAA		intron	N/A	ENSP00000307212.3	O15160-2
	XPO5	ENST00000943409.1		c.3474+118_3474+119insTT		intron	N/A	ENSP00000613468.1

Frequencies

GnomAD3 genomes AF: 0.000253 AC: 24 AN: 94998 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000746

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000118

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: 0.0000236

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00314 AC: 3039 AN: 969308 Hom.: 0 AF XY: 0.00305 AC XY: 1451 AN XY: 476356

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

African (AFR) AF: 0.00296 AC: 63 AN: 21318

American (AMR) AF: 0.00308 AC: 50 AN: 16234

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 69 AN: 15780

East Asian (EAS) AF: 0.00316 AC: 95 AN: 30062

South Asian (SAS) AF: 0.00389 AC: 192 AN: 49410

European-Finnish (FIN) AF: 0.00136 AC: 43 AN: 31632

Middle Eastern (MID) AF: 0.00317 AC: 9 AN: 2842

European-Non Finnish (NFE) AF: 0.00314 AC: 2386 AN: 760272

Other (OTH) AF: 0.00316 AC: 132 AN: 41758

⚠️ 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: 0.000253 AC: 24 AN: 94996 Hom.: 0 Cov.: 26 AF XY: 0.000268 AC XY: 12 AN XY: 44810

African (AFR) AF: 0.000745 AC: 22 AN: 29522

American (AMR) AF: 0.000118 AC: 1 AN: 8472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2318

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2888

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.0000237 AC: 1 AN: 42282

Other (OTH) AF: 0.00 AC: 0 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		-0.39

Splicing

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

Other links and lift over

dbSNP: rs368583529; hg19: chr6-43492090;