1-161544752-A-C

Variant names:

• chr1-161544752-A-C
• rs396991
• NM_000569.8:c.526T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8307 hom., cov: 30)
  • Exomes 𝑓: 0.32 (78722 hom.)
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.375
• Publications: 560 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

ENSG00000273112 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.526T>G	p.Phe176Val	missense_variant	Exon 4 of 5	ENST00000443193.6	NP_000560.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6	c.526T>G	p.Phe176Val	missense_variant	Exon 4 of 5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.*55T>G		downstream_gene_variant				ENSP00000514363.1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 49910 AN: 151126 Hom.: 8283 Cov.: 30

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

GnomAD2 exomes AF: 0.325 AC: 80158 AN: 246638 AF XY: 0.330

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 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

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

African (AFR) AF: 0.329 AC: 10650 AN: 32368

American (AMR) AF: 0.246 AC: 10907 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10563 AN: 25534

East Asian (EAS) AF: 0.301 AC: 11801 AN: 39256

South Asian (SAS) AF: 0.338 AC: 28732 AN: 84950

European-Finnish (FIN) AF: 0.271 AC: 14449 AN: 53230

Middle Eastern (MID) AF: 0.432 AC: 2424 AN: 5614

European-Non Finnish (NFE) AF: 0.319 AC: 334839 AN: 1049792

Other (OTH) AF: 0.332 AC: 19283 AN: 58094

⚠️ 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: 0.330 AC: 49964 AN: 151244 Hom.: 8307 Cov.: 30 AF XY: 0.329 AC XY: 24287 AN XY: 73876

African (AFR) AF: 0.335 AC: 13813 AN: 41262

American (AMR) AF: 0.288 AC: 4375 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1404 AN: 3442

East Asian (EAS) AF: 0.327 AC: 1675 AN: 5128

South Asian (SAS) AF: 0.332 AC: 1593 AN: 4796

European-Finnish (FIN) AF: 0.268 AC: 2822 AN: 10520

Middle Eastern (MID) AF: 0.441 AC: 127 AN: 288

European-Non Finnish (NFE) AF: 0.342 AC: 23091 AN: 67616

Other (OTH) AF: 0.344 AC: 720 AN: 2096

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely 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: 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) -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
DEOGEN2	Benign	0.015	.;T;T;T;.;.
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
MutationAssessor	Benign	0.16	.;N;N;N;.;.
PhyloP100		-0.38
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.7	N;.;N;N;.;.
REVEL	Benign	0.064
Sift	Benign	1.0	T;.;T;T;.;.
Sift4G	Benign	0.13	.;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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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