3-46021447-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001024644.2(XCR1):c.501C>G(p.Phe167Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: XCR1 NM_001024644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

XCR1 (HGNC:1625): (X-C motif chemokine receptor 1) The protein encoded by this gene is a chemokine receptor belonging to the G protein-coupled receptor superfamily. The family members are characterized by the presence of 7 transmembrane domains. The encoded protein transduces a signal by increasing the intracellular calcium ion level. The viral macrophage inflammatory protein-II is an antagonist of this receptor and blocks signaling. Some studies have implicated a cluster of genes at 3p21.31, including this gene, as associated with COVID-19 risk. The encoded protein may also play a role in cell proliferation and migration in several types of cancer. [provided by RefSeq, Jan 2023]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XCR1	NM_001024644.2	c.501C>G	p.Phe167Leu	missense_variant	2/2	ENST00000309285.4
XCR1	NM_001381860.1	c.501C>G	p.Phe167Leu	missense_variant	4/4
XCR1	NM_005283.3	c.501C>G	p.Phe167Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XCR1	ENST00000309285.4	c.501C>G	p.Phe167Leu	missense_variant	2/2	1	NM_001024644.2	P1
XCR1	ENST00000395946.3	c.501C>G	p.Phe167Leu	missense_variant	3/3	1		P1
XCR1	ENST00000683768.1	c.501C>G	p.Phe167Leu	missense_variant	6/6			P1

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.501C>G (p.F167L) alteration is located in exon 3 (coding exon 1) of the XCR1 gene. This alteration results from a C to G substitution at nucleotide position 501, causing the phenylalanine (F) at amino acid position 167 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.0055
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.29
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.044	B
Vest4		0.31
MutPred		0.74		Loss of ubiquitination at K169 (P = 0.0787);
MVP		0.68
MPC		0.94
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.44

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: chr3-46062939;