10-93593825-T-C

Variant names:

• chr10-93593825-T-C
• rs750356617
• NM_006744.4:c.566A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_006744.4(RBP4):​c.566A>G​(p.Asn189Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,459,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N189N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RBP4 NM_006744.4 missense, splice_region
• Scores: Splicing: ADA: 0.002226
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.59
• 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 1 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 1 benign (89%) 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=0.22590029).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBP4	NM_006744.4	c.566A>G	p.Asn189Ser	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.566A>G	p.Asn189Ser	missense_variant, splice_region_variant	Exon 5 of 6		NP_001310446.1
RBP4	NM_001323518.2	c.560A>G	p.Asn187Ser	missense_variant, splice_region_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.566A>G	p.Asn189Ser	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_006744.4	ENSP00000360519.3
RBP4	ENST00000371467.5	c.566A>G	p.Asn189Ser	missense_variant, splice_region_variant	Exon 5 of 6	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.560A>G	p.Asn187Ser	missense_variant, splice_region_variant	Exon 5 of 6	5		ENSP00000360524.2
FFAR4	ENST00000604414.1	c.697-10249T>C		intron_variant	Intron 2 of 2	3		ENSP00000474477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250596 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1459328 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726018

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

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: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4282

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111830

Other (OTH) AF: 0.0000332 AC: 2 AN: 60220

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566A>G (p.N189S) alteration is located in exon 5 (coding exon 4) of the RBP4 gene. This alteration results from a A to G substitution at nucleotide position 566, causing the asparagine (N) at amino acid position 189 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 189 of the RBP4 protein (p.Asn189Ser). This variant is present in population databases (rs750356617, gnomAD 0.003%). 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: 839508). 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T;T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	.;T;T;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.5	L;L;.;.
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.63	T;T;.;T
Sift4G	Benign	0.74	T;T;T;T
Polyphen		0.28	B;B;.;.
Vest4		0.47
MutPred		0.54		Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);.;.;
MVP		0.54
MPC		0.49
ClinPred		0.12	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.47
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0022
dbscSNV1_RF	Benign	0.094
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: rs750356617; hg19: chr10-95353582;