8-21995572-A-C

Variant names:

• chr8-21995572-A-C
• NM_015024.5:c.2318A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015024.5(XPO7):​c.2318A>C​(p.Lys773Thr) 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: 32)
• Consequence: XPO7 NM_015024.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18

Genes affected

XPO7 (HGNC:14108): (exportin 7) The transport of protein and large RNAs through the nuclear pore complexes (NPC) is an energy-dependent and regulated process. The import of proteins with a nuclear localization signal (NLS) is accomplished by recognition of one or more clusters of basic amino acids by the importin-alpha/beta complex; see MIM 600685 and MIM 602738. The small GTPase RAN (MIM 601179) plays a key role in NLS-dependent protein import. RAN-binding protein-16 is a member of the importin-beta superfamily of nuclear transport receptors.[supplied by OMIM, Jul 2002]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPO7	NM_015024.5	c.2318A>C	p.Lys773Thr	missense_variant	Exon 21 of 28	ENST00000252512.14	NP_055839.3
XPO7	NM_001100161.2	c.2345A>C	p.Lys782Thr	missense_variant	Exon 21 of 28		NP_001093631.1
XPO7	NM_001362802.2	c.2252A>C	p.Lys751Thr	missense_variant	Exon 20 of 27		NP_001349731.1
XPO7	NR_156173.2	n.2538A>C		non_coding_transcript_exon_variant	Exon 22 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPO7	ENST00000252512.14	c.2318A>C	p.Lys773Thr	missense_variant	Exon 21 of 28	1	NM_015024.5	ENSP00000252512.9
XPO7	ENST00000433566.8	c.2321A>C	p.Lys774Thr	missense_variant	Exon 21 of 28	5		ENSP00000410249.3
XPO7	ENST00000517551.2	c.248A>C	p.Lys83Thr	missense_variant	Exon 3 of 6	5		ENSP00000429317.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2318A>C (p.K773T) alteration is located in exon 21 (coding exon 21) of the XPO7 gene. This alteration results from a A to C substitution at nucleotide position 2318, causing the lysine (K) at amino acid position 773 to be replaced by a threonine (T). 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	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.020	D
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.93
MVP		0.42
MPC		1.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.80

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-21853083;