1-180787774-A-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.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 NM_004736.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79

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 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 where missense usually causes diseases, XPR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.36923808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XPR1	NM_004736.4	c.143A>G	p.Lys48Arg	missense_variant	3/15	ENST00000367590.9
XPR1	NM_001135669.2	c.143A>G	p.Lys48Arg	missense_variant	3/14
XPR1	NM_001328662.2	c.143A>G	p.Lys48Arg	missense_variant	3/11
XPR1	NR_137330.2	n.323A>G		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XPR1	ENST00000367590.9	c.143A>G	p.Lys48Arg	missense_variant	3/15	1	NM_004736.4	P1
XPR1	ENST00000367589.3	c.143A>G	p.Lys48Arg	missense_variant	3/14	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460606 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726618

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.: 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

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
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	D
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.

Other links and lift over

hg19: chr1-180756910;