NM_000569.8:c.216G>A

Variant names:

• chr1-161548524-C-T
• rs114535887
• NM_000569.8:c.216G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000569.8(FCGR3A):​c.216G>A​(p.Ser72Ser) 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
• Publications: 7 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.067).
• BP6: Variant 1-161548524-C-T is Benign according to our data. Variant chr1-161548524-C-T is described in ClinVar as Benign. ClinVar VariationId 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.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCGR3A	NM_000569.8	c.216G>A	p.Ser72Ser	synonymous_variant	Exon 3 of 5	ENST00000443193.6	NP_000560.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCGR3A	ENST00000443193.6	c.216G>A	p.Ser72Ser	synonymous_variant	Exon 3 of 5	1	NM_000569.8	ENSP00000392047.2
ENSG00000289768	ENST00000699402.1	c.213G>A	p.Ser71Ser	synonymous_variant	Exon 3 of 4			ENSP00000514363.1

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

GnomAD2 exomes AF: 0.0399 AC: 10008 AN: 251028 AF XY: 0.0413

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 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

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

African (AFR) AF: 0.00831 AC: 278 AN: 33470

American (AMR) AF: 0.0228 AC: 1018 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 2371 AN: 26050

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39696

South Asian (SAS) AF: 0.0310 AC: 2672 AN: 86234

European-Finnish (FIN) AF: 0.0608 AC: 3246 AN: 53374

Middle Eastern (MID) AF: 0.0515 AC: 297 AN: 5762

European-Non Finnish (NFE) AF: 0.0496 AC: 55124 AN: 1110462

Other (OTH) AF: 0.0477 AC: 2876 AN: 60332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

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

African (AFR) AF: 0.00913 AC: 379 AN: 41530

American (AMR) AF: 0.0303 AC: 463 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 298 AN: 3440

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.0303 AC: 146 AN: 4814

European-Finnish (FIN) AF: 0.0597 AC: 631 AN: 10568

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0478 AC: 3241 AN: 67754

Other (OTH) AF: 0.0400 AC: 84 AN: 2102

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0430 Hom.: 4

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.53
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114535887; hg19: chr1-161518314;