chr1-161548524-C-T

Position:

• chr1-161548524-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000569.8(FCGR3A):​c.216G>A​(p.Ser72=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,611,932 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (2 hom., cov: 37)
  • Exomes 𝑓: 0.046 (8 hom.)
• Consequence: FCGR3A NM_000569.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.515

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-161548524-C-T is Benign according to our data. Variant chr1-161548524-C-T is described in ClinVar as [Benign]. Clinvar id is 402856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.515 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0349 (5297/151862) while in subpopulation NFE AF= 0.0478 (3241/67754). AF 95% confidence interval is 0.0465. There are 2 homozygotes in gnomad4. There are 2555 alleles in male gnomad4 subpopulation. Median coverage is 37. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.216G>A	p.Ser72=	synonymous_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.216G>A	p.Ser72=	synonymous_variant	3/5	1	NM_000569.8	ENSP00000392047	P4

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5298 AN: 151744 Hom.: 2 Cov.: 37

Gnomad AFR AF: 0.00915

Gnomad AMI AF: 0.0442

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0305

Gnomad FIN AF: 0.0597

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0404

GnomAD3 exomes AF: 0.0399 AC: 10008 AN: 251028 Hom.: 0 AF XY: 0.0413 AC XY: 5605 AN XY: 135666

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0219

Gnomad ASJ exome AF: 0.0922

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0312

Gnomad FIN exome AF: 0.0599

Gnomad NFE exome AF: 0.0499

Gnomad OTH exome AF: 0.0459

GnomAD4 exome AF: 0.0465 AC: 67888 AN: 1460070 Hom.: 8 Cov.: 116 AF XY: 0.0461 AC XY: 33515 AN XY: 726438

Gnomad4 AFR exome AF: 0.00831

Gnomad4 AMR exome AF: 0.0228

Gnomad4 ASJ exome AF: 0.0910

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0310

Gnomad4 FIN exome AF: 0.0608

Gnomad4 NFE exome AF: 0.0496

Gnomad4 OTH exome AF: 0.0477

GnomAD4 genome AF: 0.0349 AC: 5297 AN: 151862 Hom.: 2 Cov.: 37 AF XY: 0.0344 AC XY: 2555 AN XY: 74254

Gnomad4 AFR AF: 0.00913

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0866

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0303

Gnomad4 FIN AF: 0.0597

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0400

Alfa AF: 0.0458 Hom.: 1

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 -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114535887; hg19: chr1-161518314;