12-64419070-T-G

Position:

• chr12-64419070-T-G

Variant summary

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

The NM_007235.6(XPOT):​c.465T>G​(p.Asp155Glu) variant causes a missense change involving the alteration of a non-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: 33)
• Consequence: XPOT NM_007235.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

Genes affected

XPOT (HGNC:12826): (exportin for tRNA) This gene encodes a protein belonging to the RAN-GTPase exportin family that mediates export of tRNA from the nucleus to the cytoplasm. Translocation of tRNA to the cytoplasm occurs once exportin has bound both tRNA and GTP-bound RAN. [provided by RefSeq, Jul 2008]

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
XPOT	NM_007235.6	c.465T>G	p.Asp155Glu	missense_variant	6/25	ENST00000332707.10	NP_009166.2
XPOT	XM_017018748.2	c.465T>G	p.Asp155Glu	missense_variant	6/25		XP_016874237.1
XPOT	XM_047428193.1	c.465T>G	p.Asp155Glu	missense_variant	6/25		XP_047284149.1
XPOT	XM_047428194.1	c.465T>G	p.Asp155Glu	missense_variant	6/15		XP_047284150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPOT	ENST00000332707.10	c.465T>G	p.Asp155Glu	missense_variant	6/25	2	NM_007235.6	ENSP00000327821	P1
XPOT	ENST00000400935.2	c.465T>G	p.Asp155Glu	missense_variant	5/6	2		ENSP00000383722

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

Dec 28, 2022

The c.465T>G (p.D155E) alteration is located in exon 6 (coding exon 5) of the XPOT gene. This alteration results from a T to G substitution at nucleotide position 465, causing the aspartic acid (D) at amino acid position 155 to be replaced by a glutamic acid (E). 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	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	0.031
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.028	D;T
Polyphen		0.66	P;.
Vest4		0.81
MutPred		0.67		Gain of catalytic residue at D150 (P = 0.0229);Gain of catalytic residue at D150 (P = 0.0229);
MVP		0.37
MPC		0.98
ClinPred		0.91	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.45

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: chr12-64812850;