NM_000569.8:c.233C>A

Variant names:

• chr1-161548507-G-T
• rs52820103
• NM_000569.8:c.233C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000569.8(FCGR3A):​c.233C>A​(p.Ala78Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 150,114 control chromosomes in the GnomAD database, including 5 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A78T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 38)
  • Exomes 𝑓: 0.00037 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.06
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052833557).
• BP6: Variant 1-161548507-G-T is Benign according to our data. Variant chr1-161548507-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3387944.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.233C>A	p.Ala78Asp	missense	Exon 3 of 5	NP_000560.7
	FCGR3A	NM_001127592.2		c.545C>A	p.Ala182Asp	missense	Exon 3 of 5	NP_001121064.2	P08637
	FCGR3A	NM_001329122.1		c.548C>A	p.Ala183Asp	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.233C>A	p.Ala78Asp	missense	Exon 3 of 5	ENSP00000392047.2	P08637
	ENSG00000289768	ENST00000699402.1		c.230C>A	p.Ala77Asp	missense	Exon 3 of 4	ENSP00000514363.1	A0A8V8TN80
	FCGR3A	ENST00000946731.1		c.233C>A	p.Ala78Asp	missense	Exon 3 of 6	ENSP00000616790.1

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 540 AN: 150004 Hom.: 5 Cov.: 38

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000461

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00389

GnomAD2 exomes AF: 0.000807 AC: 202 AN: 250384 AF XY: 0.000562

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000375 AC: 547 AN: 1458874 Hom.: 5 Cov.: 116 AF XY: 0.000306 AC XY: 222 AN XY: 725766

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

African (AFR) AF: 0.0147 AC: 475 AN: 32358

American (AMR) AF: 0.000313 AC: 14 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85694

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53406

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5746

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1110950

Other (OTH) AF: 0.000664 AC: 40 AN: 60232

⚠️ 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 AF: 0.00360 AC: 541 AN: 150114 Hom.: 5 Cov.: 38 AF XY: 0.00350 AC XY: 257 AN XY: 73478

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

African (AFR) AF: 0.0132 AC: 525 AN: 39742

American (AMR) AF: 0.000460 AC: 7 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67878

Other (OTH) AF: 0.00385 AC: 8 AN: 2080

⚠️ 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: 0.0493 Hom.: 25

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00206 AC: 250

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.013
DANN	Benign	0.27
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.44	N
PhyloP100		-2.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.19
Sift	Benign	0.42	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.17
MPC		0.20
ClinPred		0.044	T
GERP RS		-8.9
Varity_R		0.24
gMVP		0.23
Mutation Taster		=98/2	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: rs52820103; hg19: chr1-161518297; COSMIC: COSV63459586;