10-93593847-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BS1_Supporting

The NM_006744.4(RBP4):c.544C>A(p.Gln182Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,612,186 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: RBP4 NM_006744.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.17

Genes affected

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]

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a chain Plasma retinol-binding protein(1-176) (size 175) in uniprot entity RET4_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_006744.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023739219).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000565 (86/152290) while in subpopulation NFE AF= 0.001 (68/68020). AF 95% confidence interval is 0.000808. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBP4	NM_006744.4	c.544C>A	p.Gln182Lys	missense_variant	5/6	ENST00000371464.8
RBP4	NM_001323517.1	c.544C>A	p.Gln182Lys	missense_variant	5/6
RBP4	NM_001323518.2	c.538C>A	p.Gln180Lys	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBP4	ENST00000371464.8	c.544C>A	p.Gln182Lys	missense_variant	5/6	1	NM_006744.4	P1
RBP4	ENST00000371467.5	c.544C>A	p.Gln182Lys	missense_variant	5/6	5		P1
RBP4	ENST00000371469.2	c.538C>A	p.Gln180Lys	missense_variant	5/6	5
FFAR4	ENST00000604414.1	c.697-10227G>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

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: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000598 AC: 150 AN: 250906 Hom.: 0 AF XY: 0.000612 AC XY: 83 AN XY: 135636

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000516

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00116 AC: 1697 AN: 1459896 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 800 AN XY: 726280

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000396

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000930

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74464

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000763

EpiControl AF: 0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2023	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 182 of the RBP4 protein (p.Gln182Lys). This variant is present in population databases (rs116887052, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RBP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 289619). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.544C>A (p.Q182K) alteration is located in exon 5 (coding exon 4) of the RBP4 gene. This alteration results from a C to A substitution at nucleotide position 544, causing the glutamine (Q) at amino acid position 182 to be replaced by a lysine (K). 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	Benign	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	19
Dann	Benign	0.78
DEOGEN2	Benign	0.15	T;T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.020	N;N;.;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.050	N;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.88	T;T;.;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0040	B;B;.;.
Vest4		0.26
MVP		0.27
MPC		0.77
ClinPred		0.012	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.33

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: rs116887052; hg19: chr10-95353604;