1-180632227-C-G

Position:

• chr1-180632227-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_004736.4(XPR1):​c.26C>G​(p.Ala9Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: XPR1 NM_004736.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24

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 (HGNC:):

ACMG classification

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 NM_004736.4
• 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=0.34405363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPR1	NM_004736.4	c.26C>G	p.Ala9Gly	missense_variant	1/15	ENST00000367590.9	NP_004727.2
XPR1	NM_001135669.2	c.26C>G	p.Ala9Gly	missense_variant	1/14		NP_001129141.1
XPR1	NM_001328662.2	c.26C>G	p.Ala9Gly	missense_variant	1/11		NP_001315591.1
XPR1	NR_137330.2	n.206C>G		non_coding_transcript_exon_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPR1	ENST00000367590.9	c.26C>G	p.Ala9Gly	missense_variant	1/15	1	NM_004736.4	ENSP00000356562.4
XPR1	ENST00000367589.3	c.26C>G	p.Ala9Gly	missense_variant	1/14	1		ENSP00000356561.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

GeneDx

Apr 25, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.054	T;D
Polyphen		0.81	P;P
Vest4		0.40
MutPred		0.55		Loss of stability (P = 0.0389);Loss of stability (P = 0.0389);
MVP		0.068
MPC		1.9
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.79
gMVP		0.37

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: chr1-180601363;