NM_020750.3:c.3312+15_3312+26dupCATGGGGGAAGG

Variant names:

• chr6-43524804-T-TCCTTCCCCCATG
• rs369159546
• NM_020750.3:c.3312+15_3312+26dupCATGGGGGAAGG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_020750.3(XPO5):​c.3312+15_3312+26dupCATGGGGGAAGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,611,432 control chromosomes in the GnomAD database, including 362 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (113 hom., cov: 32)
  • Exomes 𝑓: 0.015 (249 hom.)
• Consequence: XPO5 NM_020750.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.00
• 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 -10 ACMG points.

• BP6: Variant 6-43524804-T-TCCTTCCCCCATG is Benign according to our data. Variant chr6-43524804-T-TCCTTCCCCCATG is described in ClinVar as Benign. ClinVar VariationId is 1239542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0624 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.3312+15_3312+26dupCATGGGGGAAGG		intron	N/A	NP_065801.1	Q9HAV4
	POLR1C	NM_001318876.2		c.922+3765_922+3776dupCATGCCTTCCCC		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.922+3765_922+3776dupCATGCCTTCCCC		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.3312+26_3312+27insCATGGGGGAAGG		intron	N/A	ENSP00000265351.7	Q9HAV4
	POLR1C	ENST00000304004.7	TSL:1	c.922+3756_922+3757insCCTTCCCCCATG		intron	N/A	ENSP00000307212.3	O15160-2
	XPO5	ENST00000943409.1		c.3309+26_3309+27insCATGGGGGAAGG		intron	N/A	ENSP00000613468.1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4052 AN: 152064 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0111 AC: 2757 AN: 248072 AF XY: 0.0103

Gnomad AFR exome AF: 0.0631

Gnomad AMR exome AF: 0.00421

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00382

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0149 AC: 21807 AN: 1459252 Hom.: 249 Cov.: 33 AF XY: 0.0143 AC XY: 10376 AN XY: 725868

African (AFR) AF: 0.0678 AC: 2266 AN: 33420

American (AMR) AF: 0.00548 AC: 245 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00667 AC: 174 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86146

European-Finnish (FIN) AF: 0.00411 AC: 219 AN: 53348

Middle Eastern (MID) AF: 0.00618 AC: 29 AN: 4690

European-Non Finnish (NFE) AF: 0.0161 AC: 17898 AN: 1111032

Other (OTH) AF: 0.0147 AC: 886 AN: 60184

GnomAD4 genome AF: 0.0268 AC: 4076 AN: 152180 Hom.: 113 Cov.: 32 AF XY: 0.0248 AC XY: 1842 AN XY: 74414

African (AFR) AF: 0.0645 AC: 2674 AN: 41472

American (AMR) AF: 0.0143 AC: 219 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00165 AC: 8 AN: 4834

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1005 AN: 68012

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.00509 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs369159546; hg19: chr6-43492542;