19-54874299-A-G

Position:

• chr19-54874299-A-G

Variant summary

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

The NM_002000.4(FCAR):​c.10A>G​(p.Lys4Glu) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FCAR NM_002000.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.528

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 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=0.067653835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCAR	NM_002000.4	c.10A>G	p.Lys4Glu	missense_variant	1/5	ENST00000355524.8	NP_001991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCAR	ENST00000355524.8	c.10A>G	p.Lys4Glu	missense_variant	1/5	1	NM_002000.4	ENSP00000347714.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

May 02, 2024

The c.10A>G (p.K4E) alteration is located in exon 1 (coding exon 1) of the FCAR gene. This alteration results from a A to G substitution at nucleotide position 10, causing the lysine (K) at amino acid position 4 to be replaced by a glutamic acid (E). 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	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.011	.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.051	N
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.068	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.76	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.75	N;.;N;N;N;N;N;N;N
REVEL	Benign	0.018
Sift	Uncertain	0.020	D;.;T;T;T;D;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T
Polyphen		0.60, 0.16, 0.89	.;P;B;.;P;.;.;.;.
Vest4		0.15
MutPred		0.32		Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);Loss of ubiquitination at K4 (P = 0.0224);
MVP		0.26
MPC		0.10
ClinPred		0.11	T
GERP RS		1.7
Varity_R		0.067
gMVP		0.33

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: chr19-55385755;