3-46020998-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001024644.2(XCR1):c.950C>T(p.Ser317Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,612,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: XCR1 NM_001024644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.672

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03567639).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XCR1	NM_001024644.2	c.950C>T	p.Ser317Leu	missense_variant	2/2	ENST00000309285.4
XCR1	NM_001381860.1	c.950C>T	p.Ser317Leu	missense_variant	4/4
XCR1	NM_005283.3	c.950C>T	p.Ser317Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XCR1	ENST00000309285.4	c.950C>T	p.Ser317Leu	missense_variant	2/2	1	NM_001024644.2	P1
XCR1	ENST00000395946.3	c.950C>T	p.Ser317Leu	missense_variant	3/3	1		P1
XCR1	ENST00000683768.1	c.950C>T	p.Ser317Leu	missense_variant	6/6			P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000243 AC: 6 AN: 247312 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 133882

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460602 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 726538

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Mar 22, 2023

The c.950C>T (p.S317L) alteration is located in exon 3 (coding exon 1) of the XCR1 gene. This alteration results from a C to T substitution at nucleotide position 950, causing the serine (S) at amino acid position 317 to be replaced by a leucine (L). 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	0.092
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	5.3
Dann	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.035
Sift	Benign	0.038	D
Sift4G	Benign	0.082	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.30		Loss of glycosylation at S317 (P = 0.0046);
MVP		0.18
MPC		0.31
ClinPred		0.028	T
GERP RS		1.5
Varity_R		0.036
gMVP		0.28

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: rs529280793; hg19: chr3-46062490; COSMIC: COSV58569807; COSMIC: COSV58569807;