chr1-161518015-T-G

Variant names:

• chr1-161518015-T-G
• rs382627
• NM_001136219.3:c.821T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136219.3(FCGR2A):​c.821T>G​(p.Leu274Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,371,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: FCGR2A NM_001136219.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131
• Publications: 23 publications found

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]

ENSG00000273112 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05073127).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136219.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR2A	NM_001136219.3	MANE Select	c.821T>G	p.Leu274Arg	missense	Exon 7 of 7	NP_001129691.1
	FCGR2A	NM_021642.5		c.818T>G	p.Leu273Arg	missense	Exon 7 of 7	NP_067674.2
	FCGR2A	NM_001375296.1		c.698T>G	p.Leu233Arg	missense	Exon 6 of 6	NP_001362225.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCGR2A	ENST00000271450.12	TSL:1 MANE Select	c.821T>G	p.Leu274Arg	missense	Exon 7 of 7	ENSP00000271450.6
	FCGR2A	ENST00000367972.8	TSL:1	c.818T>G	p.Leu273Arg	missense	Exon 7 of 7	ENSP00000356949.4
	FCGR2A	ENST00000699277.1		c.698T>G	p.Leu233Arg	missense	Exon 6 of 6	ENSP00000514258.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000417 AC: 1 AN: 239870 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 5 AN: 1371256 Hom.: 0 Cov.: 31 AF XY: 0.00000294 AC XY: 2 AN XY: 679912

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

African (AFR) AF: 0.00 AC: 0 AN: 30930

American (AMR) AF: 0.00 AC: 0 AN: 38390

Ashkenazi Jewish (ASJ) AF: 0.0000441 AC: 1 AN: 22688

East Asian (EAS) AF: 0.00 AC: 0 AN: 34834

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5340

European-Non Finnish (NFE) AF: 0.00000283 AC: 3 AN: 1058616

Other (OTH) AF: 0.00 AC: 0 AN: 55280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000805303), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.4
DANN	Benign	0.42
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.13
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.092
Sift	Benign	0.055	T
Sift4G	Benign	0.28	T
Polyphen		0.068	B
Vest4		0.20
MutPred		0.37		Loss of catalytic residue at L274 (P = 0.0139)
MVP		0.22
MPC		2.3
ClinPred		0.053	T
GERP RS		-1.4
Varity_R		0.18
gMVP		0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs382627; hg19: chr1-161487805;