8-21999163-T-G

Variant names:

• chr8-21999163-T-G
• NM_015024.5:c.2501T>G

Variant summary

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

The NM_015024.5(XPO7):​c.2501T>G​(p.Ile834Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 8.02

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XPO7	NM_015024.5	c.2501T>G	p.Ile834Ser	missense_variant	Exon 23 of 28	ENST00000252512.14	NP_055839.3
XPO7	NM_001100161.2	c.2528T>G	p.Ile843Ser	missense_variant	Exon 23 of 28		NP_001093631.1
XPO7	NM_001362802.2	c.2435T>G	p.Ile812Ser	missense_variant	Exon 22 of 27		NP_001349731.1
XPO7	NR_156173.2	n.2721T>G		non_coding_transcript_exon_variant	Exon 24 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XPO7	ENST00000252512.14	c.2501T>G	p.Ile834Ser	missense_variant	Exon 23 of 28	1	NM_015024.5	ENSP00000252512.9
XPO7	ENST00000433566.8	c.2504T>G	p.Ile835Ser	missense_variant	Exon 23 of 28	5		ENSP00000410249.3
XPO7	ENST00000517551.2	c.431T>G	p.Ile144Ser	missense_variant	Exon 5 of 6	5		ENSP00000429317.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2501T>G (p.I834S) alteration is located in exon 23 (coding exon 23) of the XPO7 gene. This alteration results from a T to G substitution at nucleotide position 2501, causing the isoleucine (I) at amino acid position 834 to be replaced by a serine (S). 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	0.73
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.4	D;D;.
REVEL	Uncertain	0.31
Sift	Benign	0.046	D;D;.
Sift4G	Benign	0.079	T;T;D
Polyphen		0.0040	B;B;.
Vest4		0.88
MVP		0.19
MPC		0.76
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.55
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr8-21856674;