rs10127939

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.00

Variant links:

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]

FCGR3A links:

ENSG00000289768 (HGNC:):

ENSG00000289768 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
FCGR3A	NM_000569.8 linkuse as main transcript	c.197T>G	p.Leu66Arg	missense_variant	3/5	ENST00000443193.6	NP_000560.7	P08637

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6 linkuse as main transcript	c.197T>G	p.Leu66Arg	missense_variant	3/5	1	NM_000569.8	ENSP00000392047.2		P08637
ENSG00000289768	ENST00000699402.1 linkuse as main transcript	c.194T>G	p.Leu65Arg	missense_variant	3/4			ENSP00000514363.1		A0A8V8TN80

Frequencies

GnomAD3 genomes

AF:

0.0507

AC:

7687

AN:

151526

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0443

AC XY:

6003

AN XY:

135638

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.0506

AC XY:

3752

AN XY:

74130

show subpopulations

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.:

ExAC

AF:

0.0458

AC:

5565

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 24782186, 8609432) -

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.66

DANN

Benign

0.79

DEOGEN2

Benign

0.045

.;T;T;T;.;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.019

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

MutationAssessor

Benign

1.6

.;L;L;L;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.6

.;.;D;D;D;.;D

REVEL

Benign

0.10

Sift

Benign

0.16

.;.;T;T;D;.;T

Sift4G

Benign

0.53

.;T;T;T;.;.;.

Polyphen

0.097

.;B;B;B;.;.;.

Vest4

0.089

MPC

0.28

ClinPred

0.015

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over