Genetic Variant XCR1:p.Ala330Thr (chr3-46020960-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001024644.2(XCR1):c.988G>A(p.Ala330Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,611,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

XCR1
NM_001024644.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.104

Publications

2 publications found

Variant links:

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]

XCR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035830855).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XCR1	NM_001024644.2	MANE Select	c.988G>A	p.Ala330Thr	missense	Exon 2 of 2	NP_001019815.1	P46094
XCR1	NM_001381860.1		c.988G>A	p.Ala330Thr	missense	Exon 4 of 4	NP_001368789.1	P46094
XCR1	NM_005283.3		c.988G>A	p.Ala330Thr	missense	Exon 3 of 3	NP_005274.1	P46094

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XCR1	ENST00000309285.4	TSL:1 MANE Select	c.988G>A	p.Ala330Thr	missense	Exon 2 of 2	ENSP00000310405.3	P46094
XCR1	ENST00000395946.3	TSL:1	c.988G>A	p.Ala330Thr	missense	Exon 3 of 3	ENSP00000379277.3	P46094
XCR1	ENST00000683768.1		c.988G>A	p.Ala330Thr	missense	Exon 6 of 6	ENSP00000507745.1	P46094

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.0000368

AC:

AN:

244690

AF XY:

0.0000378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1459546

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.000157

AC:

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26016

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.0000582

AC:

AN:

85866

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1110904

Other (OTH)

AF:

0.0000332

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.050

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.58

M_CAP

Benign

0.030

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.10

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.21

REVEL

Benign

0.069

Sift

Benign

0.37

Sift4G

Benign

0.55

Polyphen

0.49

Vest4

0.028

MutPred

0.16

Gain of glycosylation at A330 (P = 0.0187)

MVP

0.50

MPC

0.35

ClinPred

0.041

GERP RS

3.8

Varity_R

0.034

gMVP

0.43

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over