chr1-161543152-C-A

Variant names:

• chr1-161543152-C-A
• rs1212676969
• NM_000569.8:c.625G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000569.8(FCGR3A):​c.625G>T​(p.Val209Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V209L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FCGR3A NM_000569.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.164
• Publications: 0 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

ENSG00000273112 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13922495).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000569.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR3A	NM_000569.8	MANE Select	c.625G>T	p.Val209Phe	missense	Exon 5 of 5	NP_000560.7
	FCGR3A	NM_001127592.2		c.937G>T	p.Val313Phe	missense	Exon 5 of 5	NP_001121064.2	P08637
	FCGR3A	NM_001329122.1		c.682G>T	p.Val228Phe	missense	Exon 4 of 4	NP_001316051.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR3A	ENST00000443193.6	TSL:1 MANE Select	c.625G>T	p.Val209Phe	missense	Exon 5 of 5	ENSP00000392047.2	P08637
	FCGR3A	ENST00000946731.1		c.700G>T	p.Val234Phe	missense	Exon 6 of 6	ENSP00000616790.1
	FCGR3A	ENST00000699401.1		c.792G>T	p.Lys264Asn	missense	Exon 6 of 6	ENSP00000514362.1	A0A8V8TQ03

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461400 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727016

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111662

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.93	L
PhyloP100		-0.16
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.13	T
Polyphen		0.62	P
Vest4		0.38
MVP		0.081
MPC		0.41
ClinPred		0.63	D
GERP RS		-2.5
Varity_R		0.26
gMVP		0.34
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1212676969; hg19: chr1-161512942;