1-180787802-G-C

Position:

• chr1-180787802-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004736.4(XPR1):​c.171G>C​(p.Lys57Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPR1 NM_004736.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• 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=0.19505098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPR1	NM_004736.4	c.171G>C	p.Lys57Asn	missense_variant	3/15	ENST00000367590.9	NP_004727.2
XPR1	NM_001135669.2	c.171G>C	p.Lys57Asn	missense_variant	3/14		NP_001129141.1
XPR1	NM_001328662.2	c.171G>C	p.Lys57Asn	missense_variant	3/11		NP_001315591.1
XPR1	NR_137330.2	n.351G>C		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPR1	ENST00000367590.9	c.171G>C	p.Lys57Asn	missense_variant	3/15	1	NM_004736.4	ENSP00000356562	P1
XPR1	ENST00000367589.3	c.171G>C	p.Lys57Asn	missense_variant	3/14	1		ENSP00000356561

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 57 of the XPR1 protein (p.Lys57Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with XPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2103309). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XPR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.042
Sift	Benign	0.30	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0070	B;B
Vest4		0.43
MutPred		0.48		Loss of methylation at K57 (P = 0.0126);Loss of methylation at K57 (P = 0.0126);
MVP		0.043
MPC		0.97
ClinPred		0.18	T
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.14
gMVP		0.50

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: chr1-180756938;