19-51823818-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002030.5(FPR3):c.70G>A(p.Val24Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: FPR3 NM_002030.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.324

Genes affected

FPR3 (HGNC:3828): (formyl peptide receptor 3) Predicted to enable N-formyl peptide receptor activity and complement receptor activity. Predicted to be involved in several processes, including complement receptor mediated signaling pathway; phospholipase C-activating G protein-coupled receptor signaling pathway; and positive regulation of cytosolic calcium ion concentration. Predicted to act upstream of or within G protein-coupled receptor signaling pathway. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZNF577 (HGNC:28673): (zinc finger protein 577) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018193364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FPR3	NM_002030.5	c.70G>A	p.Val24Ile	missense_variant	2/2	ENST00000339223.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FPR3	ENST00000339223.5	c.70G>A	p.Val24Ile	missense_variant	2/2	1	NM_002030.5	P1
FPR3	ENST00000595991.1	c.70G>A	p.Val24Ile	missense_variant	2/2	4		P1
ZNF577	ENST00000638827.1	c.*600-12144C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 251032 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135668

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461650 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727126

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74290

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000127 Hom.: 0

Bravo AF: 0.000204

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.70G>A (p.V24I) alteration is located in exon 2 (coding exon 1) of the FPR3 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the valine (V) at amino acid position 24 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	3.1
Dann	Benign	0.90
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0028	N
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.63	N;.
REVEL	Benign	0.0050
Sift	Benign	0.14	T;.
Sift4G	Benign	0.26	T;T
Polyphen		0.060	B;B
Vest4		0.022
MutPred		0.38		Loss of disorder (P = 0.2106);Loss of disorder (P = 0.2106);
MVP		0.099
MPC		0.22
ClinPred		0.016	T
GERP RS		-0.60
Varity_R		0.032
gMVP		0.34

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: rs774486058; hg19: chr19-52327071;