10-93593828-T-C

Variant names:

• chr10-93593828-T-C
• rs758050576
• NM_006744.4:c.563A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_006744.4(RBP4):​c.563A>G​(p.His188Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: RBP4 NM_006744.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99
• Publications: 0 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: Uncertain_significance. The variant received 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBP4	NM_006744.4	c.563A>G	p.His188Arg	missense_variant	Exon 5 of 6	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.563A>G	p.His188Arg	missense_variant	Exon 5 of 6		NP_001310446.1
RBP4	NM_001323518.2	c.557A>G	p.His186Arg	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.563A>G	p.His188Arg	missense_variant	Exon 5 of 6	1	NM_006744.4	ENSP00000360519.3
RBP4	ENST00000371467.5	c.563A>G	p.His188Arg	missense_variant	Exon 5 of 6	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.557A>G	p.His186Arg	missense_variant	Exon 5 of 6	5		ENSP00000360524.2
FFAR4	ENST00000604414.1	c.697-10246T>C		intron_variant	Intron 2 of 2	3		ENSP00000474477.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250638 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459408 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726058

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44710

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: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4302

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111836

Other (OTH) AF: 0.0000166 AC: 1 AN: 60226

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000568 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1019998). This variant has not been reported in the literature in individuals affected with RBP4-related conditions. This variant is present in population databases (rs758050576, gnomAD 0.002%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 188 of the RBP4 protein (p.His188Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;.
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.4	M;M;.;.
PhyloP100		8.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.027	D;D;.;D
Sift4G	Uncertain	0.029	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.76
MutPred		0.63		Gain of MoRF binding (P = 0.0023);Gain of MoRF binding (P = 0.0023);.;.;
MVP		0.76
MPC		1.7
ClinPred		0.95	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.81
Mutation Taster		=9/91	disease causing

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: rs758050576; hg19: chr10-95353585;