10-93593823-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PP2PP3_StrongBS1_Supporting

The NM_006744.4(RBP4):​c.568G>A​(p.Gly190Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000946 in 1,459,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

RBP4
NM_006744.4 missense, splice_region

Scores

5
10
4
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84

Publications

0 publications found
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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 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.
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BS1
Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000946 (138/1459232) while in subpopulation NFE AF = 0.000116 (129/1111832). AF 95% confidence interval is 0.0000993. There are 0 homozygotes in GnomAdExome4. There are 66 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RBP4NM_006744.4 linkc.568G>A p.Gly190Ser missense_variant, splice_region_variant Exon 5 of 6 ENST00000371464.8 NP_006735.2 P02753
RBP4NM_001323517.1 linkc.568G>A p.Gly190Ser missense_variant, splice_region_variant Exon 5 of 6 NP_001310446.1 P02753
RBP4NM_001323518.2 linkc.562G>A p.Gly188Ser missense_variant, splice_region_variant Exon 5 of 6 NP_001310447.1 P02753Q5VY30

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RBP4ENST00000371464.8 linkc.568G>A p.Gly190Ser missense_variant, splice_region_variant Exon 5 of 6 1 NM_006744.4 ENSP00000360519.3 P02753
RBP4ENST00000371467.5 linkc.568G>A p.Gly190Ser missense_variant, splice_region_variant Exon 5 of 6 5 ENSP00000360522.1 P02753
RBP4ENST00000371469.2 linkc.562G>A p.Gly188Ser missense_variant, splice_region_variant Exon 5 of 6 5 ENSP00000360524.2 Q5VY30
FFAR4ENST00000604414.1 linkc.697-10251C>T intron_variant Intron 2 of 2 3 ENSP00000474477.1 S4R3L2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
250478
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000946
AC:
138
AN:
1459232
Hom.:
0
Cov.:
32
AF XY:
0.0000909
AC XY:
66
AN XY:
725988
show subpopulations
African (AFR)
AF:
0.0000898
AC:
3
AN:
33412
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86168
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52806
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4252
European-Non Finnish (NFE)
AF:
0.000116
AC:
129
AN:
1111832
Other (OTH)
AF:
0.0000830
AC:
5
AN:
60216
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.461
Heterozygous variant carriers
0
8
17
25
34
42
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000658
Hom.:
0
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 190 of the RBP4 protein (p.Gly190Ser). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, 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: 1413985). 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 disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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
0.18
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;T;T;T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.84
.;T;T;.
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.46
T;T;T;T
MetaSVM
Uncertain
0.26
D
MutationAssessor
Pathogenic
3.0
M;M;.;.
PhyloP100
7.8
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.3
D;D;.;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0050
D;D;.;D
Sift4G
Uncertain
0.016
D;D;D;D
Polyphen
1.0
D;D;.;.
Vest4
0.41
MVP
0.72
MPC
1.5
ClinPred
0.98
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.64
gMVP
0.69
Mutation Taster
=17/83
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1009832282; hg19: chr10-95353580; API