3-46021442-T-G

Position:

• chr3-46021442-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001024644.2(XCR1):​c.506A>C​(p.Lys169Thr) 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. 16/21 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: 1.80

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09088504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XCR1	NM_001024644.2	c.506A>C	p.Lys169Thr	missense_variant	2/2	ENST00000309285.4
XCR1	NM_001381860.1	c.506A>C	p.Lys169Thr	missense_variant	4/4
XCR1	NM_005283.3	c.506A>C	p.Lys169Thr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XCR1	ENST00000309285.4	c.506A>C	p.Lys169Thr	missense_variant	2/2	1	NM_001024644.2	P1
XCR1	ENST00000395946.3	c.506A>C	p.Lys169Thr	missense_variant	3/3	1		P1
XCR1	ENST00000683768.1	c.506A>C	p.Lys169Thr	missense_variant	6/6			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 09, 2023

The c.506A>C (p.K169T) alteration is located in exon 3 (coding exon 1) of the XCR1 gene. This alteration results from a A to C substitution at nucleotide position 506, causing the lysine (K) at amino acid position 169 to be replaced by a threonine (T). 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	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.1
DANN	Benign	0.68
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.51	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.15
Sift	Benign	0.23	T
Sift4G	Benign	0.33	T
Polyphen		0.034	B
Vest4		0.071
MutPred		0.67		Loss of methylation at K169 (P = 0.0126);
MVP		0.58
MPC		0.43
ClinPred		0.23	T
GERP RS		1.5
Varity_R		0.096
gMVP		0.37

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: rs1708144736; hg19: chr3-46062934;