NM_006744.4:c.544C>A

Variant names:

• chr10-93593847-G-T
• rs116887052
• NM_006744.4:c.544C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 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. 17/22 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
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a chain Plasma retinol-binding protein(1-179) (size 178) in uniprot entity RET4_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_006744.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.77539 (below the threshold of 3.09). Trascript score misZ: 0.86182 (below the threshold of 3.09). GenCC associations: The gene is linked to progressive retinal dystrophy due to retinol transport defect, microphthalmia, isolated, with coloboma 10, isolated anophthalmia-microphthalmia syndrome, microphthalmia, isolated, with coloboma.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBP4	NM_006744.4	c.544C>A	p.Gln182Lys	missense_variant	Exon 5 of 6	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.544C>A	p.Gln182Lys	missense_variant	Exon 5 of 6		NP_001310446.1
RBP4	NM_001323518.2	c.538C>A	p.Gln180Lys	missense_variant	Exon 5 of 6		NP_001310447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBP4	ENST00000371464.8	c.544C>A	p.Gln182Lys	missense_variant	Exon 5 of 6	1	NM_006744.4	ENSP00000360519.3
RBP4	ENST00000371467.5	c.544C>A	p.Gln182Lys	missense_variant	Exon 5 of 6	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.538C>A	p.Gln180Lys	missense_variant	Exon 5 of 6	5		ENSP00000360524.2
FFAR4	ENST00000604414.1	c.697-10227G>T		intron_variant	Intron 2 of 2	3		ENSP00000474477.1

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

GnomAD2 exomes AF: 0.000598 AC: 150 AN: 250906 AF XY: 0.000612

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33426

American (AMR) AF: 0.000201 AC: 9 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.000396 AC: 21 AN: 53076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4552

European-Non Finnish (NFE) AF: 0.00144 AC: 1600 AN: 1111880

Other (OTH) AF: 0.000930 AC: 56 AN: 60238

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

African (AFR) AF: 0.000337 AC: 14 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000998 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

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". 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. -

Jul 27, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Benign	0.84	.;T;T;.
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;.;.
PhyloP100		3.2
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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs116887052; hg19: chr10-95353604;