10-93593865-C-T

Variant names:

• chr10-93593865-C-T
• rs2058283703
• NM_006744.4:c.526G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_006744.4(RBP4):​c.526G>A​(p.Glu176Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E176D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBP4 NM_006744.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89
• 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 5 ACMG points.

• PM1: In a disulfide_bond (size 156) in uniprot entity RET4_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_006744.4
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBP4	NM_006744.4	c.526G>A	p.Glu176Lys	missense_variant	Exon 5 of 6	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.526G>A	p.Glu176Lys	missense_variant	Exon 5 of 6		NP_001310446.1
RBP4	NM_001323518.2	c.520G>A	p.Glu174Lys	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.526G>A	p.Glu176Lys	missense_variant	Exon 5 of 6	1	NM_006744.4	ENSP00000360519.3
RBP4	ENST00000371467.5	c.526G>A	p.Glu176Lys	missense_variant	Exon 5 of 6	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.520G>A	p.Glu174Lys	missense_variant	Exon 5 of 6	5		ENSP00000360524.2
FFAR4	ENST00000604414.1	c.697-10209C>T		intron_variant	Intron 2 of 2	3		ENSP00000474477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D;.
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.2	M;M;.;.
PhyloP100		4.9
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D;D;.;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		0.95	P;P;.;.
Vest4		0.56
MutPred		0.59		Gain of MoRF binding (P = 0.0029);Gain of MoRF binding (P = 0.0029);.;.;
MVP		0.57
MPC		1.5
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.43
Mutation Taster		=85/15	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: rs2058283703; hg19: chr10-95353622; COSMIC: COSV65160600; COSMIC: COSV65160600;