NM_002030.5:c.278T>C

Variant names:

• chr19-51824026-T-C
• NM_002030.5:c.278T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002030.5(FPR3):​c.278T>C​(p.Phe93Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FPR3 NM_002030.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002030.5. 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
	FPR3	NM_002030.5	MANE Select	c.278T>C	p.Phe93Ser	missense	Exon 2 of 2	NP_002021.3
	ZNF577	NR_163433.1		n.2153-10049A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FPR3	ENST00000339223.5	TSL:1 MANE Select	c.278T>C	p.Phe93Ser	missense	Exon 2 of 2	ENSP00000341821.3	P25089
	FPR3	ENST00000595991.1	TSL:4	c.278T>C	p.Phe93Ser	missense	Exon 2 of 2	ENSP00000470471.1	P25089
	FPR3	ENST00000901092.1		c.278T>C	p.Phe93Ser	missense	Exon 2 of 2	ENSP00000571151.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

⚠️ 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: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0027	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.1
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.90		Gain of disorder (P = 0.0099)
MVP		0.72
MPC		1.2
ClinPred		1.0	D
GERP RS		2.2
Varity_R		0.89
gMVP		0.54
Mutation Taster		=74/26	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

hg19: chr19-52327279;