3-46021146-C-T

Variant names:

• chr3-46021146-C-T
• rs761692588
• NM_001024644.2:c.802G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001024644.2(XCR1):​c.802G>A​(p.Ala268Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: XCR1 NM_001024644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XCR1	NM_001024644.2	c.802G>A	p.Ala268Thr	missense_variant	Exon 2 of 2	ENST00000309285.4	NP_001019815.1
XCR1	NM_001381860.1	c.802G>A	p.Ala268Thr	missense_variant	Exon 4 of 4		NP_001368789.1
XCR1	NM_005283.3	c.802G>A	p.Ala268Thr	missense_variant	Exon 3 of 3		NP_005274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XCR1	ENST00000309285.4	c.802G>A	p.Ala268Thr	missense_variant	Exon 2 of 2	1	NM_001024644.2	ENSP00000310405.3
XCR1	ENST00000395946.3	c.802G>A	p.Ala268Thr	missense_variant	Exon 3 of 3	1		ENSP00000379277.3
XCR1	ENST00000683768.1	c.802G>A	p.Ala268Thr	missense_variant	Exon 6 of 6			ENSP00000507745.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.802G>A (p.A268T) alteration is located in exon 3 (coding exon 1) of the XCR1 gene. This alteration results from a G to A substitution at nucleotide position 802, causing the alanine (A) at amino acid position 268 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	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.25
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.33
MutPred		0.88		Loss of stability (P = 0.0299);
MVP		0.34
MPC		1.1
ClinPred		0.79	D
GERP RS		3.8
Varity_R		0.13
gMVP		0.46

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: rs761692588; hg19: chr3-46062638; COSMIC: COSV100499511; COSMIC: COSV100499511;