NM_006744.4:c.569-1G>A

Variant names:

• chr10-93592113-C-T
• rs2058270689
• NM_006744.4:c.569-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006744.4(RBP4):​c.569-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBP4 NM_006744.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.23
• Publications: 0 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-93592113-C-T is Pathogenic according to our data. Variant chr10-93592113-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929566.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBP4	NM_006744.4	c.569-1G>A		splice_acceptor_variant, intron_variant	Intron 5 of 5	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.569-1G>A		splice_acceptor_variant, intron_variant	Intron 5 of 5		NP_001310446.1
RBP4	NM_001323518.2	c.563-1G>A		splice_acceptor_variant, intron_variant	Intron 5 of 5		NP_001310447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBP4	ENST00000371464.8	c.569-1G>A		splice_acceptor_variant, intron_variant	Intron 5 of 5	1	NM_006744.4	ENSP00000360519.3
FFAR4	ENST00000604414.1	c.697-11961C>T		intron_variant	Intron 2 of 2	3		ENSP00000474477.1
RBP4	ENST00000371467.5	c.569-1G>A		splice_acceptor_variant, intron_variant	Intron 5 of 5	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.563-1G>A		splice_acceptor_variant, intron_variant	Intron 5 of 5	5		ENSP00000360524.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microphthalmia, isolated, with coloboma 10 Pathogenic:1

May 15, 2020

Genetics Department, University Hospital of Toulouse

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This null variant affecting RBP4 gene c.569-1G>A, p.? was never reported in the literature and is absent from GnomAD. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		3.2
GERP RS		5.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.94		Position offset: -1

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

Other links and lift over

dbSNP: rs2058270689; hg19: chr10-95351870;