ENST00000604414.1:c.697-2243C>G

Variant names:

• chr10-93601831-C-G
• rs3758539
• ENST00000604414.1:c.697-2243C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000604414.1(FFAR4):​c.697-2243C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 420,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: FFAR4 ENST00000604414.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.146
• Publications: 0 publications found

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]

RBP4 (HGNC:9922): (retinol binding protein 4) This protein belongs to the lipocalin family and is the specific carrier for retinol (vitamin A alcohol) in the blood. It delivers retinol from the liver stores to the peripheral tissues. In plasma, the RBP-retinol complex interacts with transthyretin which prevents its loss by filtration through the kidney glomeruli. A deficiency of vitamin A blocks secretion of the binding protein posttranslationally and results in defective delivery and supply to the epidermal cells. [provided by RefSeq, Jul 2008]

RBP4 Gene-Disease associations (from GenCC):

• progressive retinal dystrophy due to retinol transport defect

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P
• microphthalmia, isolated, with coloboma 10

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000604414.1. 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
	RBP4	NM_001323518.2		c.-115G>C		upstream_gene	N/A	NP_001310447.1	Q5VY30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FFAR4	ENST00000604414.1	TSL:3	c.697-2243C>G		intron	N/A	ENSP00000474477.1	S4R3L2
	RBP4	ENST00000854001.1		c.-19+121G>C		intron	N/A	ENSP00000524060.1
	RBP4	ENST00000854004.1		c.-19+121G>C		intron	N/A	ENSP00000524063.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000238 AC: 1 AN: 420576 Hom.: 0 AF XY: 0.00000439 AC XY: 1 AN XY: 227810

⚠️ 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: 10570

American (AMR) AF: 0.00 AC: 0 AN: 24510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14458

East Asian (EAS) AF: 0.00 AC: 0 AN: 24412

South Asian (SAS) AF: 0.00 AC: 0 AN: 45696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2836

European-Non Finnish (NFE) AF: 0.00000409 AC: 1 AN: 244658

Other (OTH) AF: 0.00 AC: 0 AN: 23146

⚠️ 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
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.77
PhyloP100		0.15
PromoterAI		-0.030	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3758539; hg19: chr10-95361588;