1-161548424-T-C

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. 15/22 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

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

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 id 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

Gnomad4 AFR exome AF: 0.156 AC: 4407 AN: 28222

Gnomad4 AMR exome AF: 0.387 AC: 13738 AN: 35520

Gnomad4 ASJ exome AF: 0.187 AC: 4141 AN: 22194

Gnomad4 EAS exome AF: 0.432 AC: 15267 AN: 35306

Gnomad4 SAS exome AF: 0.297 AC: 21631 AN: 72898

Gnomad4 FIN exome AF: 0.269 AC: 12854 AN: 47794

Gnomad4 NFE exome AF: 0.230 AC: 209392 AN: 909676

Gnomad4 Remaining exome AF: 0.243 AC: 12346 AN: 50866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (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

Gnomad4 AFR AF: 0.179 AC: 0.179311 AN: 0.179311

Gnomad4 AMR AF: 0.329 AC: 0.329057 AN: 0.329057

Gnomad4 ASJ AF: 0.205 AC: 0.204887 AN: 0.204887

Gnomad4 EAS AF: 0.435 AC: 0.435402 AN: 0.435402

Gnomad4 SAS AF: 0.315 AC: 0.314703 AN: 0.314703

Gnomad4 FIN AF: 0.269 AC: 0.269136 AN: 0.269136

Gnomad4 NFE AF: 0.258 AC: 0.257845 AN: 0.257845

Gnomad4 OTH AF: 0.261 AC: 0.261094 AN: 0.261094

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;.;.;.
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

Publications

LitVar

Other links and lift over

dbSNP: rs148181339; hg19: chr1-161518214; COSMIC: COSV63458832;