chr19-16889821-G-A

Variant names:

• chr19-16889821-G-A
• rs773902
• NM_003950.4:c.358G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003950.4(F2RL3):​c.358G>A​(p.Ala120Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,597,532 control chromosomes in the GnomAD database, including 44,118 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9140 hom., cov: 34)
  • Exomes 𝑓: 0.21 (34978 hom.)
• Consequence: F2RL3 NM_003950.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35
• Publications: 56 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.3480874E-5).
• BP6: Variant 19-16889821-G-A is Benign according to our data. Variant chr19-16889821-G-A is described in ClinVar as Benign. ClinVar VariationId is 1182224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2RL3	NM_003950.4	MANE Select	c.358G>A	p.Ala120Thr	missense	Exon 2 of 2	NP_003941.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	F2RL3	ENST00000248076.4	TSL:1 MANE Select	c.358G>A	p.Ala120Thr	missense	Exon 2 of 2	ENSP00000248076.2
	F2RL3	ENST00000599210.1	TSL:2	c.*12G>A		3_prime_UTR	Exon 2 of 2	ENSP00000471518.1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46758 AN: 151940 Hom.: 9114 Cov.: 34

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.302

GnomAD2 exomes AF: 0.245 AC: 53808 AN: 219948 AF XY: 0.241

Gnomad AFR exome AF: 0.574

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.259

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.210 AC: 302955 AN: 1445472 Hom.: 34978 Cov.: 34 AF XY: 0.212 AC XY: 152161 AN XY: 719312

African (AFR) AF: 0.574 AC: 19171 AN: 33426

American (AMR) AF: 0.257 AC: 11310 AN: 44062

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6777 AN: 26004

East Asian (EAS) AF: 0.240 AC: 9470 AN: 39536

South Asian (SAS) AF: 0.272 AC: 23380 AN: 85812

European-Finnish (FIN) AF: 0.168 AC: 6834 AN: 40692

Middle Eastern (MID) AF: 0.344 AC: 1975 AN: 5748

European-Non Finnish (NFE) AF: 0.189 AC: 209989 AN: 1110152

Other (OTH) AF: 0.234 AC: 14049 AN: 60040

GnomAD4 genome AF: 0.308 AC: 46835 AN: 152060 Hom.: 9140 Cov.: 34 AF XY: 0.307 AC XY: 22840 AN XY: 74360

African (AFR) AF: 0.559 AC: 23168 AN: 41476

American (AMR) AF: 0.279 AC: 4271 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 910 AN: 3464

East Asian (EAS) AF: 0.253 AC: 1304 AN: 5156

South Asian (SAS) AF: 0.275 AC: 1327 AN: 4824

European-Finnish (FIN) AF: 0.176 AC: 1866 AN: 10608

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13106 AN: 67926

Other (OTH) AF: 0.307 AC: 648 AN: 2112

Alfa AF: 0.224 Hom.: 11349

Bravo AF: 0.323

TwinsUK AF: 0.193 AC: 717

ALSPAC AF: 0.191 AC: 735

ESP6500AA AF: 0.542 AC: 2354

ESP6500EA AF: 0.200 AC: 1691

ExAC AF: 0.237 AC: 28246

Asia WGS AF: 0.294 AC: 1023 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30347494, 30143503, 29748334, 25293779)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.000083	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.043
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.40	B
Vest4		0.056
MPC		0.15
ClinPred		0.0099	T
GERP RS		0.92
Varity_R		0.052
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

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: rs773902; hg19: chr19-17000632; COSMIC: COSV50185225; COSMIC: COSV50185225;