1-161548546-C-T

Variant names:

• chr1-161548546-C-T
• rs77144485
• NM_000569.8:c.194G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 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: 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
• Publications: 15 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 -16 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 VariationId is 156330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.194G>A	p.Ser65Asn	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.194G>A	p.Ser65Asn	missense_variant	Exon 3 of 5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.191G>A	p.Ser64Asn	missense_variant	Exon 3 of 4			ENSP00000514363.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 32471 AN: 127910 Hom.: 0 Cov.: 35

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

GnomAD2 exomes AF: 0.0964 AC: 17995 AN: 186676 AF XY: 0.0883

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 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

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

African (AFR) AF: 0.100 AC: 2679 AN: 26732

American (AMR) AF: 0.246 AC: 7026 AN: 28524

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 2681 AN: 21732

East Asian (EAS) AF: 0.385 AC: 12221 AN: 31772

South Asian (SAS) AF: 0.208 AC: 14402 AN: 69092

European-Finnish (FIN) AF: 0.230 AC: 9648 AN: 41912

Middle Eastern (MID) AF: 0.125 AC: 574 AN: 4580

European-Non Finnish (NFE) AF: 0.0817 AC: 71624 AN: 876334

Other (OTH) AF: 0.136 AC: 6583 AN: 48326

⚠️ 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: 0.254 AC: 32490 AN: 127974 Hom.: 0 Cov.: 35 AF XY: 0.257 AC XY: 16109 AN XY: 62600

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

African (AFR) AF: 0.214 AC: 7492 AN: 34928

American (AMR) AF: 0.321 AC: 4109 AN: 12788

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 554 AN: 2962

East Asian (EAS) AF: 0.422 AC: 1809 AN: 4288

South Asian (SAS) AF: 0.295 AC: 1167 AN: 3960

European-Finnish (FIN) AF: 0.267 AC: 2399 AN: 9000

Middle Eastern (MID) AF: 0.216 AC: 54 AN: 250

European-Non Finnish (NFE) AF: 0.248 AC: 14190 AN: 57254

Other (OTH) AF: 0.249 AC: 438 AN: 1762

⚠️ 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: 0.171 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

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	0.078
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;.;.;.
PhyloP100		-3.2
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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs77144485; hg19: chr1-161518336; COSMIC: COSV63458668;