chr10-93593863-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2

The NM_006744.4(RBP4):​c.528G>T​(p.Glu176Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,612,592 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 2 hom. )

Consequence

RBP4
NM_006744.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0250
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 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
BP4
Computational evidence support a benign effect (MetaRNN=0.10942677).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000184 (28/152200) while in subpopulation AMR AF= 0.000523 (8/15288). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RBP4NM_006744.4 linkuse as main transcriptc.528G>T p.Glu176Asp missense_variant 5/6 ENST00000371464.8
RBP4NM_001323517.1 linkuse as main transcriptc.528G>T p.Glu176Asp missense_variant 5/6
RBP4NM_001323518.2 linkuse as main transcriptc.522G>T p.Glu174Asp missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RBP4ENST00000371464.8 linkuse as main transcriptc.528G>T p.Glu176Asp missense_variant 5/61 NM_006744.4 P1
RBP4ENST00000371467.5 linkuse as main transcriptc.528G>T p.Glu176Asp missense_variant 5/65 P1
RBP4ENST00000371469.2 linkuse as main transcriptc.522G>T p.Glu174Asp missense_variant 5/65
FFAR4ENST00000604414.1 linkuse as main transcriptc.697-10211C>A intron_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
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:
0.000221
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000287
AC:
72
AN:
251128
Hom.:
0
AF XY:
0.000302
AC XY:
41
AN XY:
135746
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000467
Gnomad NFE exome
AF:
0.000475
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000392
AC:
573
AN:
1460392
Hom.:
2
Cov.:
32
AF XY:
0.000391
AC XY:
284
AN XY:
726504
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000649
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.000478
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.000955
Alfa
AF:
0.000303
Hom.:
1
Bravo
AF:
0.000283
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000264
AC:
32
EpiCase
AF:
0.000109
EpiControl
AF:
0.000474

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 18, 2022The c.528G>T (p.E176D) alteration is located in exon 5 (coding exon 4) of the RBP4 gene. This alteration results from a G to T substitution at nucleotide position 528, causing the glutamic acid (E) at amino acid position 176 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 15, 2024This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 176 of the RBP4 protein (p.Glu176Asp). This variant is present in population databases (rs150540008, gnomAD 0.05%). 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: 943659). 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
0.13
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;T;T;T
Eigen
Benign
-0.055
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.83
.;T;T;.
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
0.79
N;N;.;.
MutationTaster
Benign
0.67
D;D;D
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-1.3
N;N;.;N
REVEL
Uncertain
0.30
Sift
Benign
0.16
T;T;.;T
Sift4G
Benign
0.22
T;T;T;T
Polyphen
0.0080
B;B;.;.
Vest4
0.24
MutPred
0.46
Loss of disorder (P = 0.2157);Loss of disorder (P = 0.2157);.;.;
MVP
0.32
MPC
0.57
ClinPred
0.088
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.42
gMVP
0.33

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: rs150540008; hg19: chr10-95353620; API