rs396991

chr1-161544752-A-Cchr1-161544752-A-Gchr1-161544752-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000569.8(FCGR3A):c.526T>G(p.Phe176Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,544,462 control chromosomes in the GnomAD database, including 87,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.33 (8307 hom., cov: 30)
  • Exomes 𝑓: 0.32 (78722 hom.)
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.375

Genes affected

FCGR3A (HGNC:3619): (Fc gamma receptor IIIa) This gene encodes a receptor for the Fc portion of immunoglobulin G, and it is involved in the removal of antigen-antibody complexes from the circulation, as well as other responses, including antibody dependent cellular mediated cytotoxicity and antibody dependent enhancement of virus infections. This gene (FCGR3A) is highly similar to another nearby gene (FCGR3B) located on chromosome 1. The receptor encoded by this gene is expressed on natural killer (NK) cells as an integral membrane glycoprotein anchored through a transmembrane peptide, whereas FCGR3B is expressed on polymorphonuclear neutrophils (PMN) where the receptor is anchored through a phosphatidylinositol (PI) linkage. Mutations in this gene are associated with immunodeficiency 20, and have been linked to susceptibility to recurrent viral infections, susceptibility to systemic lupus erythematosus, and alloimmune neonatal neutropenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004077375).
• BP6: Variant 1-161544752-A-C is Benign according to our data. Variant chr1-161544752-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 225994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCGR3A	NM_000569.8	c.526T>G	p.Phe176Val	missense_variant	4/5	ENST00000443193.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCGR3A	ENST00000443193.6	c.526T>G	p.Phe176Val	missense_variant	4/5	1	NM_000569.8	P4

Frequencies

GnomAD3 genomes AF: 0.330 AC: 49910 AN: 151126 Hom.: 8283 Cov.: 30

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.442

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.343

GnomAD3 exomes AF: 0.325 AC: 80158 AN: 246638 Hom.: 13615 AF XY: 0.330 AC XY: 43997 AN XY: 133362

Gnomad AFR exome AF: 0.329

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.416

Gnomad EAS exome AF: 0.337

Gnomad SAS exome AF: 0.341

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.318 AC: 443648 AN: 1393218 Hom.: 78722 Cov.: 37 AF XY: 0.321 AC XY: 223512 AN XY: 695626

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.338

Gnomad4 FIN exome AF: 0.271

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.332

GnomAD4 genome AF: 0.330 AC: 49964 AN: 151244 Hom.: 8307 Cov.: 30 AF XY: 0.329 AC XY: 24287 AN XY: 73876

Gnomad4 AFR AF: 0.335

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.327

Gnomad4 SAS AF: 0.332

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.344

Alfa AF: 0.319 Hom.: 3321

Bravo AF: 0.334

ESP6500AA AF: 0.261 AC: 1150

ESP6500EA AF: 0.280 AC: 2412

ExAC AF: 0.331 AC: 40146

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Polymorphism that reportedly influences the strength of the antibody-dependent cellular cytotoxicity responses by NK cells. Associated with progression to end stage renal disease in lupus patients (17076550). NOT associated with suscepitibility to tuberculosis in Morrocan population (PMID 20439102) -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.12
Dann	Benign	0.38
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.073	T;.;.;T;T;T
MetaRNN	Benign	0.0041	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.7	N;.;N;N;.;.
REVEL	Benign	0.064
Sift	Benign	1.0	T;.;T;T;.;.
Polyphen		0.0	.;B;B;B;.;.
Vest4		0.070
MPC		0.17
ClinPred		0.0061	T
GERP RS		-0.10
Varity_R		0.19
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs396991; hg19: chr1-161514542; COSMIC: COSV63459276; COSMIC: COSV63459276;