10-93593832-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM2 BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.01

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a chain Plasma retinol-binding protein(1-176) (size 175) 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: {Uncertain_significance=1, Likely_benign=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
RBP4	NM_006744.4	c.559G>A	p.Val187Ile	missense_variant	5/6	ENST00000371464.8
RBP4	NM_001323517.1	c.559G>A	p.Val187Ile	missense_variant	5/6
RBP4	NM_001323518.2	c.553G>A	p.Val185Ile	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBP4	ENST00000371464.8	c.559G>A	p.Val187Ile	missense_variant	5/6	1	NM_006744.4	P1
RBP4	ENST00000371467.5	c.559G>A	p.Val187Ile	missense_variant	5/6	5		P1
RBP4	ENST00000371469.2	c.553G>A	p.Val185Ile	missense_variant	5/6	5
FFAR4	ENST00000604414.1	c.697-10242C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152168 Hom.: 0 Cov.: 32

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

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

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

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:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -

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
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

Other links and lift over

dbSNP: rs779604024; hg19: chr10-95353589;