chr10-93587284-G-A

Position:

chr10-93587284-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000371481.9(FFAR4):c.761G>A(p.Arg254His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,614,070 control chromosomes in the GnomAD database, including 393 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.014 ( 39 hom., cov: 31)

Exomes 𝑓: 0.018 ( 354 hom. )

Consequence

FFAR4
ENST00000371481.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

FFAR4 (HGNC:19061): (free fatty acid receptor 4) This gene encodes a G protein-coupled receptor (GPR) which belongs to the rhodopsin family of GPRs. The encoded protein functions as a receptor for free fatty acids, including omega-3, and participates in suppressing anti-inflammatory responses and insulin sensitizing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

FFAR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002275765).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0143 (2180/152256) while in subpopulation SAS AF= 0.0399 (192/4810). AF 95% confidence interval is 0.0353. There are 39 homozygotes in gnomad4. There are 1061 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FFAR4	NM_001195755.2 linkuse as main transcript	c.761G>A	p.Arg254His	missense_variant	3/3	ENST00000371481.9	NP_001182684.1
FFAR4	NM_181745.4 linkuse as main transcript	c.809G>A	p.Arg270His	missense_variant	4/4		NP_859529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FFAR4	ENST00000371481.9 linkuse as main transcript	c.761G>A	p.Arg254His	missense_variant	3/3	1	NM_001195755.2	ENSP00000360536	P1	Q5NUL3-2
FFAR4	ENST00000371483.8 linkuse as main transcript	c.809G>A	p.Arg270His	missense_variant	4/4	1		ENSP00000360538		Q5NUL3-1
FFAR4	ENST00000604414.1 linkuse as main transcript	c.696+11065G>A		intron_variant		3		ENSP00000474477

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2183

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00352

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.0701

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0403

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.0183

AC:

4592

AN:

251378

Hom.:

AF XY:

0.0200

AC XY:

2723

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00532

Gnomad ASJ exome

AF:

0.0601

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0335

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0177

AC:

25835

AN:

1461814

Hom.:

354

Cov.:

AF XY:

0.0187

AC XY:

13563

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.00610

Gnomad4 ASJ exome

AF:

0.0633

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0345

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.0171

Gnomad4 OTH exome

AF:

0.0188

GnomAD4 genome

AF:

0.0143

AC:

2180

AN:

152256

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1061

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00351

Gnomad4 AMR

AF:

0.00771

Gnomad4 ASJ

AF:

0.0701

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0399

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.0181

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.0196

Hom.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0174

AC:

150

ExAC

AF:

0.0193

AC:

2342

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0212

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Body mass index quantitative trait locus 10

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	May 07, 2024	The FFAR4 c.761G>A (p.Arg254His) variant, also reported as NM_181745.4:c.809G>A (p.Arg270His), has been reported as a risk allele for obesity with an odds ratio of 1.62; 95% CI 1.31-2.00 (Ichimura A et al., PMID: 22343897) and a risk allele for pathologic ALT levels with an odds ratio of 3.2, 95% CI 1.3-8.0 (adjusted for age, sex, and BMI SDS) (Marzuillo P et al., PMID: 25250621). The highest population minor allele frequency in the population database genome aggregation database (v2.1.1) is 6.03% in the Ashkenazi Jewish population. This variant may increase risk for obesity and elevated ALT levels along with other genetic and environmental factors; based on available information and the ClinGen Low Penetrance/Risk Allele Working Group recommendations (Schmidt RJ et al., PMID: 38054408) this variant is classified as an uncertain risk allele. -
risk factor, no assertion criteria provided	literature only	OMIM	Feb 19, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

.;T

Eigen

Benign

-0.028

Eigen_PC

Benign

0.091

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

2.0

.;M

MutationTaster

Benign

0.86

N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.20

Sift

Benign

0.053

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.070

B;B

Vest4

0.11

MPC

0.77

ClinPred

0.013

GERP RS

5.0

Varity_R

0.12

gMVP

0.62

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