3-46021146-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001024644.2(XCR1):​c.802G>C​(p.Ala268Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A268T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: XCR1 NM_001024644.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024644.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XCR1	NM_001024644.2	MANE Select	c.802G>C	p.Ala268Pro	missense	Exon 2 of 2	NP_001019815.1	P46094
	XCR1	NM_001381860.1		c.802G>C	p.Ala268Pro	missense	Exon 4 of 4	NP_001368789.1	P46094
	XCR1	NM_005283.3		c.802G>C	p.Ala268Pro	missense	Exon 3 of 3	NP_005274.1	P46094

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XCR1	ENST00000309285.4	TSL:1 MANE Select	c.802G>C	p.Ala268Pro	missense	Exon 2 of 2	ENSP00000310405.3	P46094
	XCR1	ENST00000395946.3	TSL:1	c.802G>C	p.Ala268Pro	missense	Exon 3 of 3	ENSP00000379277.3	P46094
	XCR1	ENST00000683768.1		c.802G>C	p.Ala268Pro	missense	Exon 6 of 6	ENSP00000507745.1	P46094

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251418 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		4.0
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.87		Loss of stability (P = 0.0597)
MVP		0.51
MPC		1.3
ClinPred		0.88	D
GERP RS		3.8
Varity_R		0.72
gMVP		0.86
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs761692588; hg19: chr3-46062638;