10-93600470-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_006744.4(RBP4):c.278G>A(p.Gly93Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G93S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RBP4 NM_006744.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.06

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 156) in uniprot entity RET4_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_006744.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 10-93600470-C-T is Pathogenic according to our data. Variant chr10-93600470-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13068.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBP4	NM_006744.4	c.278G>A	p.Gly93Asp	missense_variant	4/6	ENST00000371464.8
RBP4	NM_001323517.1	c.278G>A	p.Gly93Asp	missense_variant	4/6
RBP4	NM_001323518.2	c.272G>A	p.Gly91Asp	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBP4	ENST00000371464.8	c.278G>A	p.Gly93Asp	missense_variant	4/6	1	NM_006744.4	P1
RBP4	ENST00000371467.5	c.278G>A	p.Gly93Asp	missense_variant	4/6	5		P1
RBP4	ENST00000371469.2	c.272G>A	p.Gly91Asp	missense_variant	4/6	5
FFAR4	ENST00000604414.1	c.697-3604C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive retinal dystrophy due to retinol transport defect Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Nov 23, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.2	M;M;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.6	D;D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.75
MutPred		0.89		Gain of catalytic residue at G93 (P = 0.0763);Gain of catalytic residue at G93 (P = 0.0763);.;.;
MVP		0.84
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.99

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: rs121918585; hg19: chr10-95360227;