1-161548507-G-T

Position:

• chr1-161548507-G-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• 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

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 -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 id is 3387944.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161548507-G-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.233C>A	p.Ala78Asp	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.233C>A	p.Ala78Asp	missense_variant	3/5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.230C>A	p.Ala77Asp	missense_variant	3/4			ENSP00000514363.1

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

GnomAD3 exomes AF: 0.000807 AC: 202 AN: 250384 Hom.: 3 AF XY: 0.000562 AC XY: 76 AN XY: 135344

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 SAS 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

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.00360 AC: 541 AN: 150114 Hom.: 5 Cov.: 38 AF XY: 0.00350 AC XY: 257 AN XY: 73478

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00385

Alfa AF: 0.00813 Hom.: 2

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00206 AC: 250

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

FCGR3A: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

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;T;T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.33	T;.;.;T;T;T;T
MetaRNN	Benign	0.0053	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.44	.;N;N;N;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.76	.;.;N;N;.;.;N
REVEL	Benign	0.19
Sift	Benign	0.42	.;.;T;T;.;.;T
Sift4G	Benign	0.50	.;T;T;T;.;.;.
Polyphen		0.0	.;B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs52820103; hg19: chr1-161518297; COSMIC: COSV63459586;