1-161548546-C-T

Position:

• chr1-161548546-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000569.8(FCGR3A):​c.194G>A​(p.Ser65Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,149,004 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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: 35)
  • Exomes 𝑓: 0.11 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.24

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014047027).
• BP6: Variant 1-161548546-C-T is Benign according to our data. Variant chr1-161548546-C-T is described in ClinVar as [Benign]. Clinvar id is 156330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161548546-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.194G>A	p.Ser65Asn	missense_variant	3/5	ENST00000443193.6	NP_000560.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6	c.194G>A	p.Ser65Asn	missense_variant	3/5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.191G>A	p.Ser64Asn	missense_variant	3/4			ENSP00000514363.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 32471 AN: 127910 Hom.: 0 Cov.: 35 FAILED QC

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.211

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.0964 AC: 17995 AN: 186676 Hom.: 5 AF XY: 0.0883 AC XY: 9001 AN XY: 101962

Gnomad AFR exome AF: 0.0798

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.0438

Gnomad EAS exome AF: 0.260

Gnomad SAS exome AF: 0.0893

Gnomad FIN exome AF: 0.0799

Gnomad NFE exome AF: 0.0636

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.111 AC: 127438 AN: 1149004 Hom.: 15 Cov.: 65 AF XY: 0.117 AC XY: 67072 AN XY: 572096

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.246

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.0817

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.254 AC: 32490 AN: 127974 Hom.: 0 Cov.: 35 AF XY: 0.257 AC XY: 16109 AN XY: 62600

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.321

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.267

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.249

Alfa AF: 0.171 Hom.: 0

ExAC AF: 0.0958 AC: 11635

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.017
DANN	Benign	0.60
DEOGEN2	Benign	0.030	.;T;T;T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.28	T;.;.;T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	.;L;L;L;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	.;.;N;N;.;.;N
REVEL	Benign	0.028
Sift	Benign	0.35	.;.;T;T;.;.;T
Sift4G	Benign	0.38	.;T;T;T;.;.;.
Polyphen		0.079	.;B;B;B;.;.;.
Vest4		0.037
MPC		0.12
ClinPred		0.018	T
GERP RS		-8.9
Varity_R		0.12
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs77144485; hg19: chr1-161518336; COSMIC: COSV63458668;