NM_000569.8:c.197T>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000569.8(FCGR3A):​c.197T>A​(p.Leu66His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,612,026 control chromosomes in the GnomAD database, including 732 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L66R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.050 (100 hom., cov: 38)
  • Exomes 𝑓: 0.066 (632 hom.)
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U: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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023146272).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000569.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR3A	NM_000569.8	MANE Select	c.197T>A	p.Leu66His	missense	Exon 3 of 5	NP_000560.7
	FCGR3A	NM_001127592.2		c.509T>A	p.Leu170His	missense	Exon 3 of 5	NP_001121064.2
	FCGR3A	NM_001329122.1		c.512T>A	p.Leu171His	missense	Exon 3 of 4	NP_001316051.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR3A	ENST00000443193.6	TSL:1 MANE Select	c.197T>A	p.Leu66His	missense	Exon 3 of 5	ENSP00000392047.2
	ENSG00000289768	ENST00000699402.1		c.194T>A	p.Leu65His	missense	Exon 3 of 4	ENSP00000514363.1
	FCGR3A	ENST00000699401.1		c.197T>A	p.Leu66His	missense	Exon 4 of 6	ENSP00000514362.1

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7659 AN: 151798 Hom.: 100 Cov.: 38

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0730

Gnomad OTH AF: 0.0602

GnomAD2 exomes AF: 0.0554 AC: 13908 AN: 250992 AF XY: 0.0567

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0393

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.0765

Gnomad OTH exome AF: 0.0710

GnomAD4 exome AF: 0.0659 AC: 96231 AN: 1460108 Hom.: 632 Cov.: 125 AF XY: 0.0653 AC XY: 47469 AN XY: 726392

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

African (AFR) AF: 0.0103 AC: 344 AN: 33468

American (AMR) AF: 0.0418 AC: 1869 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3441 AN: 26072

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0216 AC: 1861 AN: 86230

European-Finnish (FIN) AF: 0.0616 AC: 3287 AN: 53396

Middle Eastern (MID) AF: 0.0634 AC: 365 AN: 5758

European-Non Finnish (NFE) AF: 0.0733 AC: 81380 AN: 1110454

Other (OTH) AF: 0.0610 AC: 3683 AN: 60330

⚠️ 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: 0.0504 AC: 7656 AN: 151918 Hom.: 100 Cov.: 38 AF XY: 0.0498 AC XY: 3698 AN XY: 74260

African (AFR) AF: 0.0113 AC: 471 AN: 41520

American (AMR) AF: 0.0585 AC: 892 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 450 AN: 3438

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4818

European-Finnish (FIN) AF: 0.0564 AC: 597 AN: 10586

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0730 AC: 4953 AN: 67810

Other (OTH) AF: 0.0596 AC: 125 AN: 2098

Alfa AF: 0.0459 Hom.: 3

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.0762 AC: 655

ExAC AF: 0.0545 AC: 6612

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity Pathogenic:1 Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FCGR3A NM_1127593.1 exon 4 p.Leu66His (c.197T>A): This variant has been reported in the literature as homozygous in 3 individuals with recurrent infection, suggestive of NK cell defects (de Vries 1996 PMID:8874200, Jawahar 1996 PMID:8608639, Grier 2012 PMID:23006327, called c.230T>A p.Leu66His). This variant is present in 7.5% (9575/126258) of European alleles including 17 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs10127939). This variant is present in ClinVar (Variation ID:14828). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, although this variant is present at a high frequency in the general population, the presence of conflicting data on this variant suggests insufficient information for disease classification. Therefore, the clinical significance of this variant is uncertain.

Oct 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Uncertain:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

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: High frequency in the general population (5 homozygotes in ExAC), but homozygous change at this position has been reported in 3 individuals with NK cell deficiency. 2 probands had recurrent upper respiratory infections. In vitro study shows possible functional impact (PMID 23006327).

not provided Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.9
DANN	Benign	0.89
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-1.0
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.065
Sift	Benign	0.12	T
Sift4G	Benign	0.54	T
Polyphen		1.0	D
Vest4		0.079
MPC		0.33
ClinPred		0.061	T
GERP RS		0.73
Varity_R		0.30
gMVP		0.33
Mutation Taster		=100/0	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;