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rs396991

Variant summary

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

The NM_000569.8(FCGR3A):c.526T>G(p.Phe176Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,544,462 control chromosomes in the GnomAD database, including 87,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.33 ( 8307 hom., cov: 30)
Exomes 𝑓: 0.32 ( 78722 hom. )

Consequence

FCGR3A
NM_000569.8 missense

Scores

15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.375
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]

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=0.004077375).
BP6
Variant 1-161544752-A-C is Benign according to our data. Variant chr1-161544752-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 225994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FCGR3ANM_000569.8 linkuse as main transcriptc.526T>G p.Phe176Val missense_variant 4/5 ENST00000443193.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FCGR3AENST00000443193.6 linkuse as main transcriptc.526T>G p.Phe176Val missense_variant 4/51 NM_000569.8 P4

Frequencies

GnomAD3 genomes
AF:
0.330
AC:
49910
AN:
151126
Hom.:
8283
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.334
Gnomad AMI
AF:
0.379
Gnomad AMR
AF:
0.289
Gnomad ASJ
AF:
0.408
Gnomad EAS
AF:
0.326
Gnomad SAS
AF:
0.333
Gnomad FIN
AF:
0.268
Gnomad MID
AF:
0.442
Gnomad NFE
AF:
0.342
Gnomad OTH
AF:
0.343
GnomAD3 exomes
AF:
0.325
AC:
80158
AN:
246638
Hom.:
13615
AF XY:
0.330
AC XY:
43997
AN XY:
133362
show subpopulations
Gnomad AFR exome
AF:
0.329
Gnomad AMR exome
AF:
0.239
Gnomad ASJ exome
AF:
0.416
Gnomad EAS exome
AF:
0.337
Gnomad SAS exome
AF:
0.341
Gnomad FIN exome
AF:
0.279
Gnomad NFE exome
AF:
0.344
Gnomad OTH exome
AF:
0.341
GnomAD4 exome
AF:
0.318
AC:
443648
AN:
1393218
Hom.:
78722
Cov.:
37
AF XY:
0.321
AC XY:
223512
AN XY:
695626
show subpopulations
Gnomad4 AFR exome
AF:
0.329
Gnomad4 AMR exome
AF:
0.246
Gnomad4 ASJ exome
AF:
0.414
Gnomad4 EAS exome
AF:
0.301
Gnomad4 SAS exome
AF:
0.338
Gnomad4 FIN exome
AF:
0.271
Gnomad4 NFE exome
AF:
0.319
Gnomad4 OTH exome
AF:
0.332
GnomAD4 genome
AF:
0.330
AC:
49964
AN:
151244
Hom.:
8307
Cov.:
30
AF XY:
0.329
AC XY:
24287
AN XY:
73876
show subpopulations
Gnomad4 AFR
AF:
0.335
Gnomad4 AMR
AF:
0.288
Gnomad4 ASJ
AF:
0.408
Gnomad4 EAS
AF:
0.327
Gnomad4 SAS
AF:
0.332
Gnomad4 FIN
AF:
0.268
Gnomad4 NFE
AF:
0.342
Gnomad4 OTH
AF:
0.344
Alfa
AF:
0.319
Hom.:
3321
Bravo
AF:
0.334
ESP6500AA
AF:
0.261
AC:
1150
ESP6500EA
AF:
0.280
AC:
2412
ExAC
AF:
0.331
AC:
40146

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant 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: Polymorphism that reportedly influences the strength of the antibody-dependent cellular cytotoxicity responses by NK cells. Associated with progression to end stage renal disease in lupus patients (17076550). NOT associated with suscepitibility to tuberculosis in Morrocan population (PMID 20439102) -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.69
T
BayesDel_noAF
Benign
-0.62
Cadd
Benign
0.12
Dann
Benign
0.38
Eigen
Benign
-2.2
Eigen_PC
Benign
-2.2
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.073
T;.;.;T;T;T
MetaRNN
Benign
0.0041
T;T;T;T;T;T
MetaSVM
Benign
-0.92
T
MutationTaster
Benign
1.0
P;P;P;P;P
PrimateAI
Benign
0.31
T
PROVEAN
Benign
1.7
N;.;N;N;.;.
REVEL
Benign
0.064
Sift
Benign
1.0
T;.;T;T;.;.
Polyphen
0.0
.;B;B;B;.;.
Vest4
0.070
MPC
0.17
ClinPred
0.0061
T
GERP RS
-0.10
Varity_R
0.19
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs396991; hg19: chr1-161514542; COSMIC: COSV63459276; COSMIC: COSV63459276; API