12-64420360-A-C

Position:

• chr12-64420360-A-C

Variant summary

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

The NM_007235.6(XPOT):​c.682A>C​(p.Asn228His) 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: XPOT NM_007235.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPOT	NM_007235.6	c.682A>C	p.Asn228His	missense_variant	8/25	ENST00000332707.10	NP_009166.2
XPOT	XM_017018748.2	c.682A>C	p.Asn228His	missense_variant	8/25		XP_016874237.1
XPOT	XM_047428193.1	c.682A>C	p.Asn228His	missense_variant	8/25		XP_047284149.1
XPOT	XM_047428194.1	c.682A>C	p.Asn228His	missense_variant	8/15		XP_047284150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPOT	ENST00000332707.10	c.682A>C	p.Asn228His	missense_variant	8/25	2	NM_007235.6	ENSP00000327821.5

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 21, 2022

The c.682A>C (p.N228H) alteration is located in exon 8 (coding exon 7) of the XPOT gene. This alteration results from a A to C substitution at nucleotide position 682, causing the asparagine (N) at amino acid position 228 to be replaced by a histidine (H). 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	Benign	0.074
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.28
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.75
MutPred		0.60		Gain of catalytic residue at D224 (P = 0);
MVP		0.55
MPC		1.1
ClinPred		0.86	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.32

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: chr12-64814140;