chr6-43551437-T-C

Position:

• chr6-43551437-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020750.3(XPO5):​c.1589A>G​(p.Asp530Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,612,708 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (8 hom.)
• Consequence: XPO5 NM_020750.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.55

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008276343).
• BP6: Variant 6-43551437-T-C is Benign according to our data. Variant chr6-43551437-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1316590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00651 (991/152296) while in subpopulation AFR AF= 0.0219 (908/41552). AF 95% confidence interval is 0.0207. There are 10 homozygotes in gnomad4. There are 435 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 991 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPO5	NM_020750.3	c.1589A>G	p.Asp530Gly	missense_variant	15/32	ENST00000265351.12	NP_065801.1
POLR1C	NM_001318876.2	c.945+22166T>C		intron_variant			NP_001305805.1
POLR1C	NM_001363658.2	c.*42+426T>C		intron_variant			NP_001350587.1
XPO5	NR_144392.2	n.1763A>G		non_coding_transcript_exon_variant	15/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPO5	ENST00000265351.12	c.1589A>G	p.Asp530Gly	missense_variant	15/32	1	NM_020750.3	ENSP00000265351	P1

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 991 AN: 152178 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00180 AC: 447 AN: 247826 Hom.: 1 AF XY: 0.00133 AC XY: 179 AN XY: 134474

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000994

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000766 AC: 1118 AN: 1460412 Hom.: 8 Cov.: 30 AF XY: 0.000658 AC XY: 478 AN XY: 726414

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000815

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00651 AC: 991 AN: 152296 Hom.: 10 Cov.: 32 AF XY: 0.00584 AC XY: 435 AN XY: 74476

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00150 Hom.: 3

Bravo AF: 0.00815

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0237 AC: 91

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00201 AC: 243

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.26	T
Sift4G	Uncertain	0.049	D
Polyphen		0.36	B
Vest4		0.51
MVP		0.56
MPC		0.59
ClinPred		0.025	T
GERP RS		5.4
Varity_R		0.35
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs61739889; hg19: chr6-43519174;