rs121918584

Positions:

• chr10-93600739-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006744.4(RBP4):​c.176T>A​(p.Ile59Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RBP4 NM_006744.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.28

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 10-93600739-A-T is Pathogenic according to our data. Variant chr10-93600739-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13067.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBP4	NM_006744.4	c.176T>A	p.Ile59Asn	missense_variant	3/6	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.176T>A	p.Ile59Asn	missense_variant	3/6		NP_001310446.1
RBP4	NM_001323518.2	c.170T>A	p.Ile57Asn	missense_variant	3/6		NP_001310447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBP4	ENST00000371464.8	c.176T>A	p.Ile59Asn	missense_variant	3/6	1	NM_006744.4	ENSP00000360519.3
RBP4	ENST00000371467.5	c.176T>A	p.Ile59Asn	missense_variant	3/6	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.170T>A	p.Ile57Asn	missense_variant	3/6	5		ENSP00000360524.2
FFAR4	ENST00000604414.1	c.697-3335A>T		intron_variant		3		ENSP00000474477.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459230 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive retinal dystrophy due to retinol transport defect Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 04, 2005	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 23, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 2019

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. This variant has been reported to affect RBP4 protein function (PMID: 25910211, 16157297). This variant has been observed to segregate with clinical features of autosomal recessive retinitis pigmentosa in a family (PMID: 9888420, 10232633). This variant is also known as p.Ile41Asn. ClinVar contains an entry for this variant (Variation ID: 13067). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 59 of the RBP4 protein (p.Ile59Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;.
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.8	D;D;.;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.92
MutPred		0.89		Loss of stability (P = 0.0378);Loss of stability (P = 0.0378);.;.;
MVP		0.45
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121918584; hg19: chr10-95360496;