10-93593832-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_006744.4(RBP4):​c.559G>A​(p.Val187Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,611,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

RBP4
NM_006744.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.01
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1
In a chain Retinol-binding protein 4 (size 182) in uniprot entity RET4_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_006744.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.049048483).
BP6
Variant 10-93593832-C-T is Benign according to our data. Variant chr10-93593832-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1013571.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000131 (20/152168) while in subpopulation SAS AF= 0.000414 (2/4828). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RBP4NM_006744.4 linkuse as main transcriptc.559G>A p.Val187Ile missense_variant 5/6 ENST00000371464.8
RBP4NM_001323517.1 linkuse as main transcriptc.559G>A p.Val187Ile missense_variant 5/6
RBP4NM_001323518.2 linkuse as main transcriptc.553G>A p.Val185Ile missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RBP4ENST00000371464.8 linkuse as main transcriptc.559G>A p.Val187Ile missense_variant 5/61 NM_006744.4 P1
RBP4ENST00000371467.5 linkuse as main transcriptc.559G>A p.Val187Ile missense_variant 5/65 P1
RBP4ENST00000371469.2 linkuse as main transcriptc.553G>A p.Val185Ile missense_variant 5/65
FFAR4ENST00000604414.1 linkuse as main transcriptc.697-10242C>T intron_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000104
AC:
26
AN:
250672
Hom.:
0
AF XY:
0.0000738
AC XY:
10
AN XY:
135546
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.000378
Gnomad NFE exome
AF:
0.0000970
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000106
AC:
155
AN:
1459410
Hom.:
0
Cov.:
32
AF XY:
0.0000923
AC XY:
67
AN XY:
726060
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.000359
Gnomad4 NFE exome
AF:
0.000106
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000200
Hom.:
0
Bravo
AF:
0.000125
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 12, 2024This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 187 of the RBP4 protein (p.Val187Ile). This variant is present in population databases (rs779604024, gnomAD 0.04%). 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: 1013571). 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
0.073
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
5.4
DANN
Benign
0.91
DEOGEN2
Benign
0.18
T;T;T;T
Eigen
Benign
-0.94
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.64
.;T;T;.
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.049
T;T;T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.6
L;L;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.54
N;N;.;N
REVEL
Benign
0.23
Sift
Benign
0.19
T;T;.;T
Sift4G
Benign
0.19
T;T;T;T
Polyphen
0.013
B;B;.;.
Vest4
0.16
MVP
0.47
MPC
0.49
ClinPred
0.025
T
GERP RS
0.58
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.12
gMVP
0.23

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779604024; hg19: chr10-95353589; API