1-161548543-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: -1.00

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FCGR3A links:

ENSG00000289768 (HGNC:):

ENSG00000289768 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCGR3A	NM_000569.8 link	c.197T>A	p.Leu66His	missense_variant	Exon 3 of 5	ENST00000443193.6	NP_000560.7	P08637

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6 link	c.197T>A	p.Leu66His	missense_variant	Exon 3 of 5	1	NM_000569.8	ENSP00000392047.2		P08637
ENSG00000289768	ENST00000699402.1 link	c.194T>A	p.Leu65His	missense_variant	Exon 3 of 4			ENSP00000514363.1		A0A8V8TN80

Frequencies

GnomAD3 genomes

AF:

0.0505

AC:

7659

AN:

151798

Hom.:

100

Cov.:

show subpopulations

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

show subpopulations

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

show subpopulations

⚠️ 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:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.363

Heterozygous variant carriers

6450

12900

19351

25801

32251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2988

5976

8964

11952

14940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0504

AC:

7656

AN:

151918

Hom.:

100

Cov.:

AF XY:

0.0498

AC XY:

3698

AN XY:

74260

show subpopulations

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:

AN:

5190

South Asian (SAS)

AF:

0.0205

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0564

AC:

597

AN:

10586

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0730

AC:

4953

AN:

67810

Other (OTH)

AF:

0.0596

AC:

125

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

307

614

921

1228

1535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0459

Hom.:

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0762

AC:

655

ExAC

AF:

0.0545

AC:

6612

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity

Pathogenic:1Uncertain:1

Oct 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.9

(source)

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

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

MutationAssessor

Uncertain

2.8

.;M;M;M;.;.;.

PhyloP100

-1.0

PrimateAI

Benign

0.25

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

GERP RS

0.73

Varity_R

0.30

gMVP

0.33

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over