19-54885297-G-C

Position:

• chr19-54885297-G-C

Variant summary

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

The NM_002000.4(FCAR):​c.133G>C​(p.Val45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FCAR NM_002000.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

Genes affected

FCAR (HGNC:3608): (Fc alpha receptor) This gene is a member of the immunoglobulin gene superfamily and encodes a receptor for the Fc region of IgA. The receptor is a transmembrane glycoprotein present on the surface of myeloid lineage cells such as neutrophils, monocytes, macrophages, and eosinophils, where it mediates immunologic responses to pathogens. It interacts with IgA-opsonized targets and triggers several immunologic defense processes, including phagocytosis, antibody-dependent cell-mediated cytotoxicity, and stimulation of the release of inflammatory mediators. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

FCAR (HGNC:):

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, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCAR	NM_002000.4	c.133G>C	p.Val45Leu	missense_variant	3/5	ENST00000355524.8	NP_001991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCAR	ENST00000355524.8	c.133G>C	p.Val45Leu	missense_variant	3/5	1	NM_002000.4	ENSP00000347714.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

Sep 28, 2022

The c.133G>C (p.V45L) alteration is located in exon 3 (coding exon 3) of the FCAR gene. This alteration results from a G to C substitution at nucleotide position 133, causing the valine (V) at amino acid position 45 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	0.33
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.10	.;.;T;.;.;.;.;.
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.23	N
M_CAP	Benign	0.0040	T
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;M;M;M;M;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N;.;D;N;D;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.053	T;.;D;D;D;T;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D;T
Polyphen		0.83, 0.96, 0.82	.;P;P;.;P;.;.;.
Vest4		0.51
MutPred		0.81		.;Loss of methylation at K46 (P = 0.0563);Loss of methylation at K46 (P = 0.0563);Loss of methylation at K46 (P = 0.0563);Loss of methylation at K46 (P = 0.0563);.;.;.;
MVP		0.21
MPC		0.14
ClinPred		0.41	T
GERP RS		2.1
Varity_R		0.61
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-55396709;