10-93587284-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001195755.2(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 risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (39 hom., cov: 31)
  • Exomes 𝑓: 0.018 (354 hom.)
• Consequence: FFAR4 NM_001195755.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 1.75

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]

ACMG classification

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 GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FFAR4	NM_001195755.2	c.761G>A	p.Arg254His	missense_variant	3/3	ENST00000371481.9
FFAR4	NM_181745.4	c.809G>A	p.Arg270His	missense_variant	4/4

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2183 AN: 152138 Hom.: 39 Cov.: 31

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.: 85 AF XY: 0.0200 AC XY: 2723 AN XY: 135862

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.: 33 AF XY: 0.0187 AC XY: 13563 AN XY: 727218

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.: 39 Cov.: 31 AF XY: 0.0143 AC XY: 1061 AN XY: 74454

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.: 79

Bravo AF: 0.0133

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0174 AC: 150

ExAC AF: 0.0193 AC: 2342

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0212

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Body mass index quantitative trait locus 10 Uncertain:1 Other: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	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.028
Eigen_PC	Benign	0.091
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.86	N;N
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs116454156; hg19: chr10-95347041; COSMIC: COSV65160232; COSMIC: COSV65160232;