rs786205904

Positions:

• chr1-180806529-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_004736.4(XPR1):​c.653T>C​(p.Leu218Ser) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPR1 NM_004736.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.41

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 Likely_pathogenic. Variant got 8 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 1-180806529-T-C is Pathogenic according to our data. Variant chr1-180806529-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 192306.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XPR1	NM_004736.4	c.653T>C	p.Leu218Ser	missense_variant	6/15	ENST00000367590.9	NP_004727.2
XPR1	NM_001135669.2	c.653T>C	p.Leu218Ser	missense_variant	6/14		NP_001129141.1
XPR1	NM_001328662.2	c.653T>C	p.Leu218Ser	missense_variant	6/11		NP_001315591.1
XPR1	NR_137330.2	n.833T>C		non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XPR1	ENST00000367590.9	c.653T>C	p.Leu218Ser	missense_variant	6/15	1	NM_004736.4	ENSP00000356562.4
XPR1	ENST00000367589.3	c.653T>C	p.Leu218Ser	missense_variant	6/14	1		ENSP00000356561.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Basal ganglia calcification, idiopathic, 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.71		Gain of disorder (P = 0.0039);Gain of disorder (P = 0.0039);
MVP		0.60
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs786205904; hg19: chr1-180775665;