3-46021707-C-G

Position:

• chr3-46021707-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001024644.2(XCR1):​c.241G>C​(p.Ala81Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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: 2.50

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35983187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XCR1	NM_001024644.2	c.241G>C	p.Ala81Pro	missense_variant	2/2	ENST00000309285.4	NP_001019815.1
XCR1	NM_001381860.1	c.241G>C	p.Ala81Pro	missense_variant	4/4		NP_001368789.1
XCR1	NM_005283.3	c.241G>C	p.Ala81Pro	missense_variant	3/3		NP_005274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XCR1	ENST00000309285.4	c.241G>C	p.Ala81Pro	missense_variant	2/2	1	NM_001024644.2	ENSP00000310405	P1
XCR1	ENST00000395946.3	c.241G>C	p.Ala81Pro	missense_variant	3/3	1		ENSP00000379277	P1
XCR1	ENST00000683768.1	c.241G>C	p.Ala81Pro	missense_variant	6/6			ENSP00000507745	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

Jun 21, 2023

The c.241G>C (p.A81P) alteration is located in exon 3 (coding exon 1) of the XCR1 gene. This alteration results from a G to C substitution at nucleotide position 241, causing the alanine (A) at amino acid position 81 to be replaced by a proline (P). 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	0.72
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.061
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.82	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.27	T
Polyphen		0.98	D
Vest4		0.29
MutPred		0.62		Gain of helix (P = 0.2059);
MVP		0.43
MPC		0.95
ClinPred		0.78	D
GERP RS		2.8
Varity_R		0.37
gMVP		0.75

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: chr3-46063199;