chr19-51746013-A-G

Variant names:

• chr19-51746013-A-G
• NM_002029.4:c.982T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_002029.4(FPR1):​c.982T>C​(p.Ser328Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FPR1 NM_002029.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.118
• Publications: 0 publications found

Genes affected

FPR1 (HGNC:3826): (formyl peptide receptor 1) This gene encodes a G protein-coupled receptor of mammalian phagocytic cells that is a member of the G-protein coupled receptor 1 family. The protein mediates the response of phagocytic cells to invasion of the host by microorganisms and is important in host defense and inflammation.[provided by RefSeq, Jul 2010]

FPR1 Gene-Disease associations (from GenCC):

• susceptibility to localized juvenile periodontitis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity FPR1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054881006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FPR1	NM_002029.4	c.982T>C	p.Ser328Pro	missense_variant	Exon 2 of 2	ENST00000304748.5	NP_002020.1
FPR1	NM_001193306.2	c.982T>C	p.Ser328Pro	missense_variant	Exon 3 of 3		NP_001180235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FPR1	ENST00000304748.5	c.982T>C	p.Ser328Pro	missense_variant	Exon 2 of 2	1	NM_002029.4	ENSP00000302707.3
FPR1	ENST00000594900.2	c.982T>C	p.Ser328Pro	missense_variant	Exon 3 of 3	4		ENSP00000470750.2
FPR1	ENST00000595042.5	c.982T>C	p.Ser328Pro	missense_variant	Exon 3 of 3	2		ENSP00000471493.1
FPR1	ENST00000600815.2	c.982T>C	p.Ser328Pro	missense_variant	Exon 2 of 2	3		ENSP00000472936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.982T>C (p.S328P) alteration is located in exon 2 (coding exon 1) of the FPR1 gene. This alteration results from a T to C substitution at nucleotide position 982, causing the serine (S) at amino acid position 328 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Gingival disorder Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with FPR1-related conditions. This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 328 of the FPR1 protein (p.Ser328Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.8
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.53	.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;L
PhyloP100		-0.12
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.071
Sift	Benign	0.081	.;T
Sift4G	Benign	0.32	T;T
Polyphen		0.011	B;B
Vest4		0.093
MutPred		0.18		Loss of phosphorylation at S328 (P = 0.0346);Loss of phosphorylation at S328 (P = 0.0346);
MVP		0.47
MPC		0.38
ClinPred		0.099	T
GERP RS		-0.086
Varity_R		0.17
gMVP		0.14
Mutation Taster		=88/12	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: chr19-52249266;