rs10127939

chr1-161548543-A-Cchr1-161548543-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.197T>G(p.Leu66Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0434 in 1,612,082 control chromosomes in the GnomAD database, including 540 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L66H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (65 hom., cov: 38)
  • Exomes 𝑓: 0.043 (475 hom.)
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.00

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=0.0027068257).
• BP6: Variant 1-161548543-A-C is Benign according to our data. Variant chr1-161548543-A-C is described in ClinVar as [Benign]. Clinvar id is 402857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161548543-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCGR3A	NM_000569.8	c.197T>G	p.Leu66Arg	missense_variant	3/5	ENST00000443193.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCGR3A	ENST00000443193.6	c.197T>G	p.Leu66Arg	missense_variant	3/5	1	NM_000569.8	P4

Frequencies

GnomAD3 genomes AF: 0.0507 AC: 7687 AN: 151526 Hom.: 65 Cov.: 38

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.0283

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0425

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0480

GnomAD3 exomes AF: 0.0433 AC: 10871 AN: 250992 Hom.: 25 AF XY: 0.0443 AC XY: 6003 AN XY: 135638

Gnomad AFR exome AF: 0.0731

Gnomad AMR exome AF: 0.0253

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0508

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0444

GnomAD4 exome AF: 0.0427 AC: 62350 AN: 1460436 Hom.: 475 Cov.: 125 AF XY: 0.0429 AC XY: 31142 AN XY: 726524

Gnomad4 AFR exome AF: 0.0741

Gnomad4 AMR exome AF: 0.0261

Gnomad4 ASJ exome AF: 0.0298

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0509

Gnomad4 FIN exome AF: 0.0526

Gnomad4 NFE exome AF: 0.0430

Gnomad4 OTH exome AF: 0.0414

GnomAD4 genome AF: 0.0507 AC: 7694 AN: 151646 Hom.: 65 Cov.: 38 AF XY: 0.0506 AC XY: 3752 AN XY: 74130

Gnomad4 AFR AF: 0.0733

Gnomad4 AMR AF: 0.0410

Gnomad4 ASJ AF: 0.0283

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0419

Gnomad4 FIN AF: 0.0522

Gnomad4 NFE AF: 0.0450

Gnomad4 OTH AF: 0.0494

Alfa AF: 0.0234 Hom.: 3

ExAC AF: 0.0458 AC: 5565

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2019

This variant is associated with the following publications: (PMID: 24782186, 8609432) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.66
Dann	Benign	0.79
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.46	T;.;.;T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
REVEL	Benign	0.10
Polyphen		0.097	.;B;B;B;.;.;.
Vest4		0.089
MPC		0.28
ClinPred		0.015	T
GERP RS		0.73
Varity_R		0.33
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

LitVar

Other links and lift over

dbSNP: rs10127939; hg19: chr1-161518333; COSMIC: COSV63458913;