19-16889579-C-A

Variant names:

• chr19-16889579-C-A
• rs144345671
• NM_003950.4:c.116C>A

Variant summary

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

The NM_003950.4(F2RL3):​c.116C>A​(p.Thr39Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T39M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: F2RL3 NM_003950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.870
• Publications: 0 publications found

Genes affected

F2RL3 (HGNC:3540): (F2R like thrombin or trypsin receptor 3) This gene encodes a member of the protease-activated receptor subfamily, part of the G-protein coupled receptor 1 family of proteins. The encoded receptor is proteolytically processed to reveal an extracellular N-terminal tethered ligand that binds to and activates the receptor. This receptor plays a role in blood coagulation, inflammation and response to pain. Hypomethylation at this gene may be associated with lung cancer in human patients. [provided by RefSeq, Sep 2016]

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=0.051834643).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003950.4. 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
	F2RL3	NM_003950.4	MANE Select	c.116C>A	p.Thr39Lys	missense	Exon 2 of 2	NP_003941.2	Q96RI0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2RL3	ENST00000248076.4	TSL:1 MANE Select	c.116C>A	p.Thr39Lys	missense	Exon 2 of 2	ENSP00000248076.2	Q96RI0
	F2RL3	ENST00000599210.1	TSL:2	c.112C>A	p.Arg38Ser	missense splice_region	Exon 2 of 2	ENSP00000471518.1	M0R0Y0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417884 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 700192

⚠️ 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: 32856

American (AMR) AF: 0.00 AC: 0 AN: 41546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23652

East Asian (EAS) AF: 0.00 AC: 0 AN: 39172

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089078

Other (OTH) AF: 0.00 AC: 0 AN: 58580

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.3
DANN	Benign	0.83
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.052	T
PhyloP100		-0.87
Sift4G	Benign	0.75	T
Vest4		0.10
MVP		0.17
ClinPred		0.32	T
GERP RS		-1.3
PromoterAI		0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
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

dbSNP: rs144345671; hg19: chr19-17000390;