rs148181339

Variant names:

• chr1-161548424-T-C
• rs148181339
• NM_000569.8:c.316A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000569.8(FCGR3A):​c.316A>G​(p.Ile106Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (0 hom., cov: 38)
  • Exomes 𝑓: 0.24 (18 hom.)
  • Failed GnomAD Quality Control
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.54
• Publications: 16 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=0.0019700825).
• BP6: Variant 1-161548424-T-C is Benign according to our data. Variant chr1-161548424-T-C is described in ClinVar as Benign. ClinVar VariationId is 156331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.316A>G	p.Ile106Val	missense_variant	Exon 3 of 5	ENST00000443193.6	NP_000560.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6	c.316A>G	p.Ile106Val	missense_variant	Exon 3 of 5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.313A>G	p.Ile105Val	missense_variant	Exon 3 of 4			ENSP00000514363.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 34813 AN: 138490 Hom.: 0 Cov.: 38

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.221

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.267 AC: 54634 AN: 204738 AF XY: 0.261

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.251

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.246

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.244 AC: 294808 AN: 1207530 Hom.: 18 Cov.: 84 AF XY: 0.245 AC XY: 147694 AN XY: 602250

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

African (AFR) AF: 0.156 AC: 4407 AN: 28222

American (AMR) AF: 0.387 AC: 13738 AN: 35520

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4141 AN: 22194

East Asian (EAS) AF: 0.432 AC: 15267 AN: 35306

South Asian (SAS) AF: 0.297 AC: 21631 AN: 72898

European-Finnish (FIN) AF: 0.269 AC: 12854 AN: 47794

Middle Eastern (MID) AF: 0.204 AC: 1032 AN: 5054

European-Non Finnish (NFE) AF: 0.230 AC: 209392 AN: 909676

Other (OTH) AF: 0.243 AC: 12346 AN: 50866

⚠️ 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 Data not reliable, filtered out with message: InbreedingCoeff AF: 0.252 AC: 34860 AN: 138606 Hom.: 0 Cov.: 38 AF XY: 0.256 AC XY: 17337 AN XY: 67730

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

African (AFR) AF: 0.179 AC: 6769 AN: 37750

American (AMR) AF: 0.329 AC: 4566 AN: 13876

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 654 AN: 3192

East Asian (EAS) AF: 0.435 AC: 2049 AN: 4706

South Asian (SAS) AF: 0.315 AC: 1357 AN: 4312

European-Finnish (FIN) AF: 0.269 AC: 2630 AN: 9772

Middle Eastern (MID) AF: 0.228 AC: 63 AN: 276

European-Non Finnish (NFE) AF: 0.258 AC: 15974 AN: 61952

Other (OTH) AF: 0.261 AC: 506 AN: 1938

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.266 Hom.: 0

ExAC AF: 0.298 AC: 36139

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 69. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: 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: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0010
DANN	Benign	0.30
DEOGEN2	Benign	0.026	.;T;T;T;.;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.034	T;.;.;T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.46	.;N;N;N;.;.;.
PhyloP100		-6.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.22	.;.;N;N;.;.;N
REVEL	Benign	0.026
Sift	Benign	0.54	.;.;T;T;.;.;T
Sift4G	Benign	0.20	.;T;T;T;.;.;.
Polyphen		0.0	.;B;B;B;.;.;.
Vest4		0.024
MPC		0.11
ClinPred		0.0079	T
GERP RS		-8.9
Varity_R		0.075
gMVP		0.18
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148181339; hg19: chr1-161518214; COSMIC: COSV63458832;