16-28106474-A-C

Position:

• chr16-28106474-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015171.4(XPO6):​c.2521T>G​(p.Phe841Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: XPO6 NM_015171.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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]

LOC124903669 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPO6	NM_015171.4	c.2521T>G	p.Phe841Val	missense_variant	19/24	ENST00000304658.10	NP_055986.1
XPO6	NM_001270940.2	c.2479T>G	p.Phe827Val	missense_variant	20/25		NP_001257869.1
LOC124903669	XR_007065032.1	n.90-2851A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPO6	ENST00000304658.10	c.2521T>G	p.Phe841Val	missense_variant	19/24	1	NM_015171.4	ENSP00000302790.4
XPO6	ENST00000565698.5	c.2479T>G	p.Phe827Val	missense_variant	20/25	2		ENSP00000457341.1
XPO6	ENST00000573275.1	c.230-22T>G		intron_variant		5		ENSP00000458314.1

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

May 14, 2024

The c.2521T>G (p.F841V) alteration is located in exon 19 (coding exon 19) of the XPO6 gene. This alteration results from a T to G substitution at nucleotide position 2521, causing the phenylalanine (F) at amino acid position 841 to be replaced by a valine (V). 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	0.74
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.95	.;P
Vest4		0.93
MutPred		0.61		.;Loss of stability (P = 0.1146);
MVP		0.60
MPC		1.8
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-28117795;