19-54888208-C-T

Position:

• chr19-54888208-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002000.4(FCAR):​c.563C>T​(p.Ser188Leu) 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 benign outcome for this variant. 13/21 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: -0.520

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3998903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCAR	NM_002000.4	c.563C>T	p.Ser188Leu	missense_variant	4/5	ENST00000355524.8	NP_001991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCAR	ENST00000355524.8	c.563C>T	p.Ser188Leu	missense_variant	4/5	1	NM_002000.4	ENSP00000347714.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

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

Jul 12, 2022

The c.563C>T (p.S188L) alteration is located in exon 4 (coding exon 4) of the FCAR gene. This alteration results from a C to T substitution at nucleotide position 563, causing the serine (S) at amino acid position 188 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	0.23
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.17	.;T;.;.;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.0068	N
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	.;D;D;D;D;D;D
REVEL	Benign	0.050
Sift	Benign	0.038	.;D;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T
Polyphen		0.90	P;D;.;.;.;.;.
Vest4		0.21
MutPred		0.58		Loss of glycosylation at S188 (P = 0.0168);Loss of glycosylation at S188 (P = 0.0168);Loss of glycosylation at S188 (P = 0.0168);.;.;.;.;
MVP		0.34
MPC		0.33
ClinPred		0.76	D
GERP RS		-0.83
Varity_R		0.19
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-55399575;