1-161506415-A-G

Position:

• chr1-161506415-A-G

Variant summary

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

The NM_001136219.3(FCGR2A):​c.188A>G​(p.Gln63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,706 control chromosomes in the GnomAD database, including 11,811 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (935 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10876 hom.)
• Consequence: FCGR2A NM_001136219.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.113

Genes affected

FCGR2A (HGNC:3616): (Fc gamma receptor IIa) This gene encodes one member of a family of immunoglobulin Fc receptor genes found on the surface of many immune response cells. The protein encoded by this gene is a cell surface receptor found on phagocytic cells such as macrophages and neutrophils, and is involved in the process of phagocytosis and clearing of immune complexes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004311353).
• BP6: Variant 1-161506415-A-G is Benign according to our data. Variant chr1-161506415-A-G is described in ClinVar as [Benign]. Clinvar id is 402850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCGR2A	NM_001136219.3	c.188A>G	p.Gln63Arg	missense_variant	3/7	ENST00000271450.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCGR2A	ENST00000271450.12	c.188A>G	p.Gln63Arg	missense_variant	3/7	1	NM_001136219.3	A2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15396 AN: 152072 Hom.: 933 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.108 AC: 27138 AN: 251424 Hom.: 1881 AF XY: 0.112 AC XY: 15183 AN XY: 135882

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.0686

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0892

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.116 AC: 169729 AN: 1461518 Hom.: 10876 Cov.: 32 AF XY: 0.117 AC XY: 84876 AN XY: 727068

Gnomad4 AFR exome AF: 0.0608

Gnomad4 AMR exome AF: 0.0717

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0921

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.101 AC: 15401 AN: 152188 Hom.: 935 Cov.: 32 AF XY: 0.101 AC XY: 7536 AN XY: 74420

Gnomad4 AFR AF: 0.0628

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.0858

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0800 Hom.: 1013

Bravo AF: 0.102

TwinsUK AF: 0.124 AC: 460

ALSPAC AF: 0.122 AC: 471

ESP6500AA AF: 0.0663 AC: 292

ESP6500EA AF: 0.132 AC: 1133

ExAC AF: 0.108 AC: 13063

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.143

EpiControl AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

-

- -

FCGR2A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.8
DANN	Benign	0.67
DEOGEN2	Benign	0.15	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	.;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.034
Sift	Benign	0.22	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0	B;B
Vest4		0.024
MPC		0.23
ClinPred		0.0065	T
GERP RS		1.3
Varity_R		0.33
gMVP		0.41

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: rs9427398; hg19: chr1-161476205;