10-93593868-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006744.4(RBP4):c.523G>A(p.Glu175Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RBP4 NM_006744.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a disulfide_bond (size 156) in uniprot entity RET4_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_006744.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1848104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBP4	NM_006744.4	c.523G>A	p.Glu175Lys	missense_variant	5/6	ENST00000371464.8
RBP4	NM_001323517.1	c.523G>A	p.Glu175Lys	missense_variant	5/6
RBP4	NM_001323518.2	c.517G>A	p.Glu173Lys	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBP4	ENST00000371464.8	c.523G>A	p.Glu175Lys	missense_variant	5/6	1	NM_006744.4	P1
RBP4	ENST00000371467.5	c.523G>A	p.Glu175Lys	missense_variant	5/6	5		P1
RBP4	ENST00000371469.2	c.517G>A	p.Glu173Lys	missense_variant	5/6	5
FFAR4	ENST00000604414.1	c.697-10206C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460620 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 175 of the RBP4 protein (p.Glu175Lys). This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1378995). This variant has not been reported in the literature in individuals affected with RBP4-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0086	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.25	T;T;.;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0060	B;B;.;.
Vest4		0.27
MutPred		0.49		Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);.;.;
MVP		0.57
MPC		0.68
ClinPred		0.74	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-95353625;