6-43524352-CAAAAAAAAA-CAAAAAAAA

Variant names:

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

Variant summary

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

The NM_020750.3(XPO5):​c.3477+118delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 94,942 control chromosomes in the GnomAD database, including 2,282 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (2282 hom., cov: 26)
  • Exomes 𝑓: 0.32 (178 hom.)
  • Failed GnomAD Quality Control
• Consequence: XPO5 NM_020750.3 intron
• Clinical Significance: 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-CA-C is Benign according to our data. Variant chr6-43524352-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1273091.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 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.3477+118delT		intron	N/A	NP_065801.1	Q9HAV4
	POLR1C	NM_001318876.2		c.922+3323delA		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.922+3323delA		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+118delT		intron	N/A	ENSP00000265351.7	Q9HAV4
	POLR1C	ENST00000304004.7	TSL:1	c.922+3305delA		intron	N/A	ENSP00000307212.3	O15160-2
	XPO5	ENST00000943409.1		c.3474+118delT		intron	N/A	ENSP00000613468.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 22370 AN: 94946 Hom.: 2278 Cov.: 26

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0558

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.232

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.317 AC: 300465 AN: 946980 Hom.: 178 AF XY: 0.318 AC XY: 147907 AN XY: 464926

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

African (AFR) AF: 0.355 AC: 7464 AN: 21048

American (AMR) AF: 0.317 AC: 4994 AN: 15746

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 4835 AN: 15320

East Asian (EAS) AF: 0.319 AC: 9207 AN: 28890

South Asian (SAS) AF: 0.317 AC: 15293 AN: 48198

European-Finnish (FIN) AF: 0.290 AC: 8859 AN: 30562

Middle Eastern (MID) AF: 0.327 AC: 904 AN: 2762

European-Non Finnish (NFE) AF: 0.317 AC: 235890 AN: 743716

Other (OTH) AF: 0.320 AC: 13019 AN: 40738

⚠️ 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: 0.236 AC: 22388 AN: 94942 Hom.: 2282 Cov.: 26 AF XY: 0.239 AC XY: 10686 AN XY: 44788

African (AFR) AF: 0.391 AC: 11532 AN: 29506

American (AMR) AF: 0.179 AC: 1513 AN: 8468

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 376 AN: 2316

East Asian (EAS) AF: 0.0949 AC: 278 AN: 2930

South Asian (SAS) AF: 0.233 AC: 672 AN: 2890

European-Finnish (FIN) AF: 0.192 AC: 904 AN: 4702

Middle Eastern (MID) AF: 0.220 AC: 33 AN: 150

European-Non Finnish (NFE) AF: 0.160 AC: 6765 AN: 42266

Other (OTH) AF: 0.232 AC: 289 AN: 1248

Alfa AF: 0.0397 Hom.: 27

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		-0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;