Genetic Variant FFAR3:p.Pro84Leu (chr19-35359141-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005304.5(FFAR3):c.251C>T(p.Pro84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,602,168 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: 𝑓 0.000080 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

FFAR3
NM_005304.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33

Variant links:

Genes affected

FFAR3 (HGNC:4499): (free fatty acid receptor 3) Enables G protein-coupled receptor activity. Involved in adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway and cellular response to fatty acid. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

FFAR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FFAR3	NM_005304.5 link	c.251C>T	p.Pro84Leu	missense_variant	Exon 2 of 2	ENST00000327809.5	NP_005295.1
FFAR3	XM_011526858.3 link	c.362C>T	p.Pro121Leu	missense_variant	Exon 2 of 2		XP_011525160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FFAR3	ENST00000327809.5 link	c.251C>T	p.Pro84Leu	missense_variant	Exon 2 of 2	1	NM_005304.5	ENSP00000328230.3		O14843
FFAR3	ENST00000594310.1 link	c.251C>T	p.Pro84Leu	missense_variant	Exon 1 of 1	6		ENSP00000469522.1		O14843

Frequencies

GnomAD3 genomes

AF:

0.0000796

AC:

AN:

150752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000178

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000642

AC:

AN:

249252

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

134840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000827

AC:

120

AN:

1451416

Hom.:

Cov.:

AF XY:

0.0000927

AC XY:

AN XY:

722472

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000107

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000796

AC:

AN:

150752

Hom.:

Cov.:

AF XY:

0.0000952

AC XY:

AN XY:

73550

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000178

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000253

Hom.:

ExAC

AF:

0.0000907

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.251C>T (p.P84L) alteration is located in exon 2 (coding exon 1) of the FFAR3 gene. This alteration results from a C to T substitution at nucleotide position 251, causing the proline (P) at amino acid position 84 to be replaced by a leucine (L). 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

Uncertain

0.38

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

.;D

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-0.41

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-8.4

D;.

REVEL

Benign

0.26

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;D

Vest4

0.71

MVP

0.54

ClinPred

0.98

GERP RS

4.5

Varity_R

0.79

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over