10-93600470-C-T

Variant names:

• chr10-93600470-C-T
• rs121918585
• NM_006744.4:c.278G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 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
• Publications: 8 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 11 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 microphthalmia, isolated, with coloboma 10, microphthalmia, isolated, with coloboma, progressive retinal dystrophy due to retinol transport defect, isolated anophthalmia-microphthalmia syndrome.
• 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 VariationId is 13068.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBP4	NM_006744.4	MANE Select	c.278G>A	p.Gly93Asp	missense	Exon 4 of 6	NP_006735.2	P02753
	RBP4	NM_001323517.1		c.278G>A	p.Gly93Asp	missense	Exon 4 of 6	NP_001310446.1	P02753
	RBP4	NM_001323518.2		c.272G>A	p.Gly91Asp	missense	Exon 4 of 6	NP_001310447.1	Q5VY30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBP4	ENST00000371464.8	TSL:1 MANE Select	c.278G>A	p.Gly93Asp	missense	Exon 4 of 6	ENSP00000360519.3	P02753
	RBP4	ENST00000854018.1		c.302G>A	p.Gly101Asp	missense	Exon 4 of 6	ENSP00000524077.1
	RBP4	ENST00000371467.5	TSL:5	c.278G>A	p.Gly93Asp	missense	Exon 4 of 6	ENSP00000360522.1	P02753

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Progressive retinal dystrophy due to retinol transport defect (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.89		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918585; hg19: chr10-95360227;