16-28101649-C-G

Position:

• chr16-28101649-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015171.4(XPO6):​c.3085G>C​(p.Val1029Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 33)
• Consequence: XPO6 NM_015171.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

XPO6 (HGNC:19733): (exportin 6) The protein encoded by this gene is a member of the importin-beta family. Members of this family are regulated by the GTPase Ran to mediate transport of cargo across the nuclear envelope. This protein has been shown to mediate nuclear export of profilin-actin complexes. A pseudogene of this gene is located on the long arm of chromosome 14. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

XPO6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPO6	NM_015171.4	c.3085G>C	p.Val1029Leu	missense_variant	23/24	ENST00000304658.10	NP_055986.1
XPO6	NM_001270940.2	c.3043G>C	p.Val1015Leu	missense_variant	24/25		NP_001257869.1
LOC124903669	XR_007065032.1	n.89+4071C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPO6	ENST00000304658.10	c.3085G>C	p.Val1029Leu	missense_variant	23/24	1	NM_015171.4	ENSP00000302790.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2024

The c.3085G>C (p.V1029L) alteration is located in exon 23 (coding exon 23) of the XPO6 gene. This alteration results from a G to C substitution at nucleotide position 3085, causing the valine (V) at amino acid position 1029 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	.;.;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	.;.;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.19	T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.79	.;.;P;.
Vest4		0.77
MutPred		0.25		.;.;Loss of MoRF binding (P = 0.1542);.;
MVP		0.28
MPC		0.70
ClinPred		0.74	D
GERP RS		6.2
Varity_R		0.17
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-28112970;