1-161548543-A-T

Position:

• chr1-161548543-A-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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]

ENSG00000289768 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.197T>A	p.Leu66His	missense_variant	3/5	ENST00000443193.6	NP_000560.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6	c.197T>A	p.Leu66His	missense_variant	3/5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.194T>A	p.Leu65His	missense_variant	3/4			ENSP00000514363.1

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

GnomAD3 exomes AF: 0.0554 AC: 13908 AN: 250992 Hom.: 26 AF XY: 0.0567 AC XY: 7693 AN XY: 135638

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 SAS exome AF: 0.0211

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

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0418

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0216

Gnomad4 FIN exome AF: 0.0616

Gnomad4 NFE exome AF: 0.0733

Gnomad4 OTH exome AF: 0.0610

GnomAD4 genome AF: 0.0504 AC: 7656 AN: 151918 Hom.: 100 Cov.: 38 AF XY: 0.0498 AC XY: 3698 AN XY: 74260

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0564

Gnomad4 NFE AF: 0.0730

Gnomad4 OTH AF: 0.0596

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -

not specified Uncertain:1

Uncertain significance, 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: 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

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;.;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.72	T;.;.;T;T;T;T
MetaRNN	Benign	0.0023	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.8	.;M;M;M;.;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.2	.;.;D;D;D;.;D
REVEL	Benign	0.065
Sift	Benign	0.12	.;.;T;T;D;.;T
Sift4G	Benign	0.54	.;T;T;T;.;.;.
Polyphen		1.0	.;D;D;D;.;.;.
Vest4		0.079
MPC		0.33
ClinPred		0.061	T
GERP RS		0.73
Varity_R		0.30
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: COSV63458917;