rs772994727

Variant names:

• chr3-46021013-G-A
• rs772994727
• NM_001024644.2:c.935C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-46021013-G-A
• chr3-46021013-G-C
• chr3-46021013-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001024644.2(XCR1):​c.935C>T​(p.Ala312Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign 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. A312G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: XCR1 NM_001024644.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.935C>T	p.Ala312Val	missense	Exon 2 of 2	NP_001019815.1	P46094
	XCR1	NM_001381860.1		c.935C>T	p.Ala312Val	missense	Exon 4 of 4	NP_001368789.1	P46094
	XCR1	NM_005283.3		c.935C>T	p.Ala312Val	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.935C>T	p.Ala312Val	missense	Exon 2 of 2	ENSP00000310405.3	P46094
	XCR1	ENST00000395946.3	TSL:1	c.935C>T	p.Ala312Val	missense	Exon 3 of 3	ENSP00000379277.3	P46094
	XCR1	ENST00000683768.1		c.935C>T	p.Ala312Val	missense	Exon 6 of 6	ENSP00000507745.1	P46094

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460912 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726698

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111536

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.63
DEOGEN2	Benign	0.056	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.084
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.039
MutPred		0.32		Loss of disorder (P = 0.0686)
MVP		0.16
MPC		0.35
ClinPred		0.067	T
GERP RS		1.6
Varity_R		0.046
gMVP		0.43
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.93		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772994727; hg19: chr3-46062505;