chr1-161518015-T-C

Position:

• chr1-161518015-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The ENST00000271450.12(FCGR2A):​c.821T>C​(p.Leu274Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 93,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0048 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: FCGR2A ENST00000271450.12 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131

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 -7 ACMG points.

• PM2: Variant has high frequency in the EAS(0.0101267) population. However there is too low homozygotes in high coverage region: (expected more than 15, got 0).
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043204427).
• BP6: Variant 1-161518015-T-C is Benign according to our data. Variant chr1-161518015-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0259 (2419/93258) while in subpopulation SAS AF= 0.0505 (133/2636). AF 95% confidence interval is 0.0435. There are 0 homozygotes in gnomad4. There are 1182 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FCGR2A	NM_001136219.3	c.821T>C	p.Leu274Pro	missense_variant	7/7	ENST00000271450.12	NP_001129691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FCGR2A	ENST00000271450.12	c.821T>C	p.Leu274Pro	missense_variant	7/7	1	NM_001136219.3	ENSP00000271450	A2

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 2414 AN: 93134 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.0236

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0252

Gnomad EAS AF: 0.0487

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0167

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0256

GnomAD3 exomes AF: 0.000429 AC: 103 AN: 239870 Hom.: 1 AF XY: 0.000385 AC XY: 50 AN XY: 129856

Gnomad AFR exome AF: 0.000386

Gnomad AMR exome AF: 0.000854

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.000709

Gnomad SAS exome AF: 0.000617

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.000690

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00475 AC: 5929 AN: 1247730 Hom.: 12 Cov.: 31 AF XY: 0.00486 AC XY: 2994 AN XY: 615858

Gnomad4 AFR exome AF: 0.00390

Gnomad4 AMR exome AF: 0.00995

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.00589

Gnomad4 FIN exome AF: 0.00705

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.0259 AC: 2419 AN: 93258 Hom.: 0 Cov.: 30 AF XY: 0.0258 AC XY: 1182 AN XY: 45854

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.0297

Gnomad4 ASJ AF: 0.0252

Gnomad4 EAS AF: 0.0486

Gnomad4 SAS AF: 0.0505

Gnomad4 FIN AF: 0.0167

Gnomad4 NFE AF: 0.0291

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0646 Hom.: 0

ExAC AF: 0.000346 AC: 42

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.3
DANN	Benign	0.18
DEOGEN2	Benign	0.031	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.19
Sift	Benign	0.13	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0	B;B
Vest4		0.28
MVP		0.26
MPC		2.4
ClinPred		0.0012	T
GERP RS		-1.4
Varity_R		0.20
gMVP		0.14

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: rs382627; hg19: chr1-161487805; COSMIC: COSV54837235;