rs428888

Variant names:

• chr1-161548496-C-T
• rs428888
• NM_000569.8:c.244G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000569.8(FCGR3A):​c.244G>A​(p.Asp82Asn) 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 0.0098 (8 hom., cov: 37)
  • Exomes 𝑓: 0.00084 (36 hom.)
  • Failed GnomAD Quality Control
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.79
• Publications: 21 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066061705).
• BP6: Variant 1-161548496-C-T is Benign according to our data. Variant chr1-161548496-C-T is described in ClinVar as Benign. ClinVar VariationId is 3910128.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000569.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR3A	NM_000569.8	MANE Select	c.244G>A	p.Asp82Asn	missense	Exon 3 of 5	NP_000560.7
	FCGR3A	NM_001127592.2		c.556G>A	p.Asp186Asn	missense	Exon 3 of 5	NP_001121064.2	P08637
	FCGR3A	NM_001329122.1		c.559G>A	p.Asp187Asn	missense	Exon 3 of 4	NP_001316051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR3A	ENST00000443193.6	TSL:1 MANE Select	c.244G>A	p.Asp82Asn	missense	Exon 3 of 5	ENSP00000392047.2	P08637
	ENSG00000289768	ENST00000699402.1		c.241G>A	p.Asp81Asn	missense	Exon 3 of 4	ENSP00000514363.1	A0A8V8TN80
	FCGR3A	ENST00000946731.1		c.244G>A	p.Asp82Asn	missense	Exon 3 of 6	ENSP00000616790.1

Frequencies

GnomAD3 genomes AF: 0.00980 AC: 1181 AN: 120458 Hom.: 8 Cov.: 37

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00388

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00690

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.00965

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0150

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.000670 AC: 162 AN: 241658 AF XY: 0.000558

Gnomad AFR exome AF: 0.00753

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000519

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000840 AC: 1096 AN: 1304062 Hom.: 36 Cov.: 134 AF XY: 0.000758 AC XY: 493 AN XY: 650218

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

African (AFR) AF: 0.0111 AC: 350 AN: 31528

American (AMR) AF: 0.000440 AC: 19 AN: 43184

Ashkenazi Jewish (ASJ) AF: 0.000354 AC: 8 AN: 22598

East Asian (EAS) AF: 0.000210 AC: 8 AN: 38006

South Asian (SAS) AF: 0.000530 AC: 43 AN: 81114

European-Finnish (FIN) AF: 0.000220 AC: 11 AN: 50032

Middle Eastern (MID) AF: 0.00117 AC: 6 AN: 5118

European-Non Finnish (NFE) AF: 0.000600 AC: 587 AN: 978808

Other (OTH) AF: 0.00119 AC: 64 AN: 53674

⚠️ 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: AS_VQSR AF: 0.00980 AC: 1182 AN: 120566 Hom.: 8 Cov.: 37 AF XY: 0.00991 AC XY: 587 AN XY: 59260

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

African (AFR) AF: 0.0174 AC: 615 AN: 35358

American (AMR) AF: 0.00647 AC: 80 AN: 12374

Ashkenazi Jewish (ASJ) AF: 0.00690 AC: 17 AN: 2462

East Asian (EAS) AF: 0.00542 AC: 24 AN: 4430

South Asian (SAS) AF: 0.00913 AC: 35 AN: 3834

European-Finnish (FIN) AF: 0.0126 AC: 98 AN: 7788

Middle Eastern (MID) AF: 0.0163 AC: 3 AN: 184

European-Non Finnish (NFE) AF: 0.00557 AC: 288 AN: 51744

Other (OTH) AF: 0.0117 AC: 19 AN: 1618

⚠️ 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: 0.0636 Hom.: 1

ExAC AF: 0.00141 AC: 171

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0010
DANN	Benign	0.32
DEOGEN2	Benign	0.014	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.065	N
PhyloP100		-3.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.013
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.18
MPC		0.13
ClinPred		0.015	T
GERP RS		-8.8
Varity_R		0.10
gMVP		0.22
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs428888; hg19: chr1-161518286; COSMIC: COSV63458837;