10-93600739-A-T

Variant names:

• chr10-93600739-A-T
• rs121918584
• NM_006744.4:c.176T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 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
• Publications: 9 publications found

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a disulfide_bond (size 156) in uniprot entity RET4_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_006744.4
• PM2: Very rare variant in population databases, with high coverage
• 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: 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 VariationId is 13067.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006744.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBP4	NM_006744.4	MANE Select	c.176T>A	p.Ile59Asn	missense	Exon 3 of 6	NP_006735.2
	RBP4	NM_001323517.1		c.176T>A	p.Ile59Asn	missense	Exon 3 of 6	NP_001310446.1
	RBP4	NM_001323518.2		c.170T>A	p.Ile57Asn	missense	Exon 3 of 6	NP_001310447.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBP4	ENST00000371464.8	TSL:1 MANE Select	c.176T>A	p.Ile59Asn	missense	Exon 3 of 6	ENSP00000360519.3
	RBP4	ENST00000371467.5	TSL:5	c.176T>A	p.Ile59Asn	missense	Exon 3 of 6	ENSP00000360522.1
	RBP4	ENST00000371469.2	TSL:5	c.170T>A	p.Ile57Asn	missense	Exon 3 of 6	ENSP00000360524.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110934

Other (OTH) AF: 0.00 AC: 0 AN: 60302

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

Nov 23, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 04, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Uncertain:1

Jul 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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 has been reported to affect RBP4 protein function (PMID: 25910211, 16157297). 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 v4.9

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
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.89		Loss of stability (P = 0.0378)
MVP		0.45
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.037	Neutral
Varity_R		0.94
gMVP		0.99
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs121918584; hg19: chr10-95360496;