rs794726861

Variant names:

• chr10-93600692-C-T
• rs794726861
• NM_006744.4:c.223G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3 PP5_Moderate

The NM_006744.4(RBP4):​c.223G>A​(p.Ala75Thr) 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. A75D) 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: 4.63
• Publications: 6 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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, 0.832
• PP5: Variant 10-93600692-C-T is Pathogenic according to our data. Variant chr10-93600692-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 192376.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.223G>A	p.Ala75Thr	missense_variant	Exon 3 of 6	ENST00000371464.8	NP_006735.2
RBP4	NM_001323517.1	c.223G>A	p.Ala75Thr	missense_variant	Exon 3 of 6		NP_001310446.1
RBP4	NM_001323518.2	c.217G>A	p.Ala73Thr	missense_variant	Exon 3 of 6		NP_001310447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBP4	ENST00000371464.8	c.223G>A	p.Ala75Thr	missense_variant	Exon 3 of 6	1	NM_006744.4	ENSP00000360519.3
RBP4	ENST00000371467.5	c.223G>A	p.Ala75Thr	missense_variant	Exon 3 of 6	5		ENSP00000360522.1
RBP4	ENST00000371469.2	c.217G>A	p.Ala73Thr	missense_variant	Exon 3 of 6	5		ENSP00000360524.2
FFAR4	ENST00000604414.1	c.697-3382C>T		intron_variant	Intron 2 of 2	3		ENSP00000474477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jan 30, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microphthalmia, isolated, with coloboma 10 Pathogenic:1

Apr 23, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T;T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.4	M;M;.;.
PhyloP100		4.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D;D;.;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.90
MutPred		0.63		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;.;
MVP		0.62
MPC		1.6
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.84
gMVP		0.92
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: rs794726861; hg19: chr10-95360449;