1-161506414-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_001136219.3(FCGR2A):c.187C>T(p.Gln63Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,614,092 control chromosomes in the GnomAD database, including 11,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.090 (849 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10604 hom.)
• Consequence: FCGR2A NM_001136219.3 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.500

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 -14 ACMG points.

• PM4: Stoplost variant in NM_001136219.3 Downstream stopcodon found after 320 codons.
• BP6: Variant 1-161506414-C-T is Benign according to our data. Variant chr1-161506414-C-T is described in ClinVar as [Benign]. Clinvar id is 402852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161506414-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCGR2A	NM_001136219.3	c.187C>T	p.Gln63Ter	stop_gained	3/7	ENST00000271450.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCGR2A	ENST00000271450.12	c.187C>T	p.Gln63Ter	stop_gained	3/7	1	NM_001136219.3	A2

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13645 AN: 152118 Hom.: 847 Cov.: 32

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0979

Gnomad ASJ AF: 0.252

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0847

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.104 AC: 26117 AN: 251418 Hom.: 1800 AF XY: 0.109 AC XY: 14744 AN XY: 135878

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0637

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.0890

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.114 AC: 166943 AN: 1461856 Hom.: 10604 Cov.: 32 AF XY: 0.115 AC XY: 83596 AN XY: 727228

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.0668

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0918

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.0896 AC: 13647 AN: 152236 Hom.: 849 Cov.: 32 AF XY: 0.0902 AC XY: 6714 AN XY: 74438

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.0977

Gnomad4 ASJ AF: 0.252

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0848

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.0994

Alfa AF: 0.120 Hom.: 571

Bravo AF: 0.0888

TwinsUK AF: 0.124 AC: 459

ALSPAC AF: 0.122 AC: 471

ESP6500AA AF: 0.0291 AC: 128

ESP6500EA AF: 0.132 AC: 1131

ExAC AF: 0.103 AC: 12529

Asia WGS AF: 0.0330 AC: 117 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.146

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 -

FCGR2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2020

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
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.62
Cadd	Pathogenic	28
Dann	Benign	0.81
Eigen	Benign	-0.63
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.022	N
MutationTaster	Benign	1.1e-16	P;P
Vest4		0.62
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9427397; hg19: chr1-161476204;