Variant 1-180787774-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The ENST00000367590.9(XPR1):c.143A>G(p.Lys48Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

XPR1
ENST00000367590.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.79

Variant links:

Genes affected

XPR1 (HGNC:12827): (xenotropic and polytropic retrovirus receptor 1) The protein encoded by this gene is a receptor for the xenotropic and polytropic classes of murine leukemia viruses. The encoded protein is involved in phosphate homeostasis by mediating phosphate export from the cell. Defects in this gene have been associated with idiopathic basal ganglia calcification-6. [provided by RefSeq, Jun 2016]

XPR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 235) in uniprot entity XPR1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in ENST00000367590.9

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), XPR1. . Gene score misZ 3.2335 (greater than the threshold 3.09). Trascript score misZ 4.1301 (greater than threshold 3.09). GenCC has associacion of gene with bilateral striopallidodentate calcinosis, basal ganglia calcification, idiopathic, 6.

BP4

Computational evidence support a benign effect (MetaRNN=0.36923808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
XPR1	NM_004736.4 linkuse as main transcript	c.143A>G	p.Lys48Arg	missense_variant	3/15	ENST00000367590.9	NP_004727.2
XPR1	NM_001135669.2 linkuse as main transcript	c.143A>G	p.Lys48Arg	missense_variant	3/14		NP_001129141.1
XPR1	NM_001328662.2 linkuse as main transcript	c.143A>G	p.Lys48Arg	missense_variant	3/11		NP_001315591.1
XPR1	NR_137330.2 linkuse as main transcript	n.323A>G		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPR1	ENST00000367590.9 linkuse as main transcript	c.143A>G	p.Lys48Arg	missense_variant	3/15	1	NM_004736.4	ENSP00000356562	P1	Q9UBH6-1
XPR1	ENST00000367589.3 linkuse as main transcript	c.143A>G	p.Lys48Arg	missense_variant	3/14	1		ENSP00000356561		Q9UBH6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460606

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.0068

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.95

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.069

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.94

P;P

Vest4

0.44

MutPred

0.41

Loss of ubiquitination at K48 (P = 0.0148);Loss of ubiquitination at K48 (P = 0.0148);

MVP

0.082

MPC

0.99

ClinPred

0.91

GERP RS

5.0

Varity_R

0.33

gMVP

0.23

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over