6-43524352-CAAAAAAAAA-CAAAAAAAAAA

Variant names:

• chr6-43524352-C-CA
• rs368583529
• NM_020750.3:c.3477+118dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_020750.3(XPO5):​c.3477+118dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,062,066 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (10 hom., cov: 26)
  • Exomes 𝑓: 0.072 (1 hom.)
• Consequence: XPO5 NM_020750.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 6-43524352-C-CA is Benign according to our data. Variant chr6-43524352-C-CA is described in ClinVar as Likely_benign. ClinVar VariationId is 1317562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0145 (1379/94932) while in subpopulation AFR AF = 0.0269 (795/29506). AF 95% confidence interval is 0.0254. There are 10 homozygotes in GnomAd4. There are 655 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1379 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+118dupT		intron	N/A	NP_065801.1	Q9HAV4
	POLR1C	NM_001318876.2		c.922+3323dupA		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.922+3323dupA		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+119insT		intron	N/A	ENSP00000265351.7	Q9HAV4
	POLR1C	ENST00000304004.7	TSL:1	c.922+3304_922+3305insA		intron	N/A	ENSP00000307212.3	O15160-2
	XPO5	ENST00000943409.1		c.3474+118_3474+119insT		intron	N/A	ENSP00000613468.1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 1379 AN: 94934 Hom.: 10 Cov.: 26

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00429

Gnomad AMR AF: 0.00885

Gnomad ASJ AF: 0.0479

Gnomad EAS AF: 0.00613

Gnomad SAS AF: 0.0206

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0976

Gnomad NFE AF: 0.00561

Gnomad OTH AF: 0.0145

GnomAD4 exome AF: 0.0720 AC: 69653 AN: 967134 Hom.: 1 AF XY: 0.0714 AC XY: 33916 AN XY: 475198

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

African (AFR) AF: 0.0522 AC: 1106 AN: 21206

American (AMR) AF: 0.0615 AC: 989 AN: 16090

Ashkenazi Jewish (ASJ) AF: 0.0825 AC: 1298 AN: 15742

East Asian (EAS) AF: 0.0655 AC: 1962 AN: 29936

South Asian (SAS) AF: 0.0690 AC: 3389 AN: 49100

European-Finnish (FIN) AF: 0.0472 AC: 1489 AN: 31518

Middle Eastern (MID) AF: 0.0677 AC: 192 AN: 2836

European-Non Finnish (NFE) AF: 0.0742 AC: 56329 AN: 759074

Other (OTH) AF: 0.0696 AC: 2899 AN: 41632

⚠️ 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: 0.0145 AC: 1379 AN: 94932 Hom.: 10 Cov.: 26 AF XY: 0.0146 AC XY: 655 AN XY: 44772

African (AFR) AF: 0.0269 AC: 795 AN: 29506

American (AMR) AF: 0.00886 AC: 75 AN: 8468

Ashkenazi Jewish (ASJ) AF: 0.0479 AC: 111 AN: 2318

East Asian (EAS) AF: 0.00615 AC: 18 AN: 2928

South Asian (SAS) AF: 0.0201 AC: 58 AN: 2886

European-Finnish (FIN) AF: 0.0104 AC: 49 AN: 4702

Middle Eastern (MID) AF: 0.100 AC: 15 AN: 150

European-Non Finnish (NFE) AF: 0.00563 AC: 238 AN: 42260

Other (OTH) AF: 0.0144 AC: 18 AN: 1248

Alfa AF: 0.00144 Hom.: 27

ClinVar

ClinVar submissions

Significance: Likely 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		-0.39
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;