rs786205902

Positions:

• chr1-180803571-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_004736.4(XPR1):​c.407G>A​(p.Ser136Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S136S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XPR1 NM_004736.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.42

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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.
• PP5: Variant 1-180803571-G-A is Pathogenic according to our data. Variant chr1-180803571-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192304.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-180803571-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPR1	NM_004736.4	c.407G>A	p.Ser136Asn	missense_variant	4/15	ENST00000367590.9
XPR1	NM_001135669.2	c.407G>A	p.Ser136Asn	missense_variant	4/14
XPR1	NM_001328662.2	c.407G>A	p.Ser136Asn	missense_variant	4/11
XPR1	NR_137330.2	n.587G>A		non_coding_transcript_exon_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPR1	ENST00000367590.9	c.407G>A	p.Ser136Asn	missense_variant	4/15	1	NM_004736.4	P1
XPR1	ENST00000367589.3	c.407G>A	p.Ser136Asn	missense_variant	4/14	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	0.98
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.61		Gain of ubiquitination at K132 (P = 0.2797);Gain of ubiquitination at K132 (P = 0.2797);
MVP		0.20
MPC		1.9
ClinPred		0.95	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.89

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: rs786205902; hg19: chr1-180772707;