rs10127939

Variant names:

• chr1-161548543-A-C
• rs10127939
• NM_000569.8:c.197T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-161548543-A-C
• chr1-161548543-A-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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:3
• Conservation: PhyloP100: -1.00
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289768 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 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 VariationId is 402857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.197T>G	p.Leu66Arg	missense_variant	Exon 3 of 5	ENST00000443193.6	NP_000560.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6	c.197T>G	p.Leu66Arg	missense_variant	Exon 3 of 5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.194T>G	p.Leu65Arg	missense_variant	Exon 3 of 4			ENSP00000514363.1

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

GnomAD2 exomes AF: 0.0433 AC: 10871 AN: 250992 AF XY: 0.0443

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0741 AC: 2474 AN: 33378

American (AMR) AF: 0.0261 AC: 1165 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 779 AN: 26106

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0509 AC: 4391 AN: 86222

European-Finnish (FIN) AF: 0.0526 AC: 2808 AN: 53372

Middle Eastern (MID) AF: 0.0888 AC: 511 AN: 5754

European-Non Finnish (NFE) AF: 0.0430 AC: 47723 AN: 1110864

Other (OTH) AF: 0.0414 AC: 2496 AN: 60336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0733 AC: 3017 AN: 41142

American (AMR) AF: 0.0410 AC: 626 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 98 AN: 3458

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0419 AC: 202 AN: 4822

European-Finnish (FIN) AF: 0.0522 AC: 552 AN: 10584

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3055 AN: 67872

Other (OTH) AF: 0.0494 AC: 104 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0234 Hom.: 3

ExAC AF: 0.0458 AC: 5565

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
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	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
MutationAssessor	Benign	1.6	.;L;L;L;.;.;.
PhyloP100		-1.0
PrimateAI	Benign	0.25	T
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	T
GERP RS		0.73
Varity_R		0.33
gMVP		0.33
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

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