6-43523597-T-C

Variant names:

• chr6-43523597-T-C
• rs55671916
• NM_020750.3:c.*271A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_020750.3(XPO5):​c.*271A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 659,036 control chromosomes in the GnomAD database, including 1,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (184 hom., cov: 32)
  • Exomes 𝑓: 0.053 (875 hom.)
• Consequence: XPO5 NM_020750.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0390
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 6-43523597-T-C is Benign according to our data. Variant chr6-43523597-T-C is described in ClinVar as Benign. ClinVar VariationId is 1227838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0639 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.*271A>G		3_prime_UTR	Exon 32 of 32	NP_065801.1	Q9HAV4
	POLR1C	NM_001318876.2		c.922+2549T>C		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.922+2549T>C		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.*271A>G		3_prime_UTR	Exon 32 of 32	ENSP00000265351.7	Q9HAV4
	POLR1C	ENST00000304004.7	TSL:1	c.922+2549T>C		intron	N/A	ENSP00000307212.3	O15160-2
	XPO5	ENST00000943409.1		c.*271A>G		3_prime_UTR	Exon 32 of 32	ENSP00000613468.1

Frequencies

GnomAD3 genomes AF: 0.0436 AC: 6629 AN: 152210 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0384

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0445

Gnomad FIN AF: 0.0543

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0655

Gnomad OTH AF: 0.0455

GnomAD4 exome AF: 0.0529 AC: 26819 AN: 506708 Hom.: 875 Cov.: 5 AF XY: 0.0528 AC XY: 14680 AN XY: 278282

African (AFR) AF: 0.0108 AC: 158 AN: 14612

American (AMR) AF: 0.0369 AC: 1408 AN: 38194

Ashkenazi Jewish (ASJ) AF: 0.0368 AC: 597 AN: 16208

East Asian (EAS) AF: 0.000864 AC: 22 AN: 25470

South Asian (SAS) AF: 0.0394 AC: 2552 AN: 64834

European-Finnish (FIN) AF: 0.0608 AC: 2396 AN: 39434

Middle Eastern (MID) AF: 0.0316 AC: 83 AN: 2628

European-Non Finnish (NFE) AF: 0.0655 AC: 18340 AN: 279910

Other (OTH) AF: 0.0497 AC: 1263 AN: 25418

GnomAD4 genome AF: 0.0435 AC: 6627 AN: 152328 Hom.: 184 Cov.: 32 AF XY: 0.0427 AC XY: 3182 AN XY: 74504

African (AFR) AF: 0.0112 AC: 466 AN: 41580

American (AMR) AF: 0.0430 AC: 658 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 133 AN: 3468

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5182

South Asian (SAS) AF: 0.0445 AC: 215 AN: 4832

European-Finnish (FIN) AF: 0.0543 AC: 577 AN: 10628

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0655 AC: 4455 AN: 68014

Other (OTH) AF: 0.0450 AC: 95 AN: 2112

Alfa AF: 0.0610 Hom.: 118

Bravo AF: 0.0398

Asia WGS AF: 0.0330 AC: 116 AN: 3478

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
BayesDel_noAF	Benign	-0.29
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		-0.039
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs55671916; hg19: chr6-43491335;