rs11204213

chr10-47351134-G-Achr10-47351134-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002900.3(RBP3):c.2650G>A(p.Val884Met) variant causes a missense change. The variant allele was found at a frequency of 0.0023 in 1,613,042 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V884L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (37 hom.)
• Consequence: RBP3 NM_002900.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.86

Genes affected

RBP3 (HGNC:9921): (retinol binding protein 3) Interphotoreceptor retinol-binding protein is a large glycoprotein known to bind retinoids and found primarily in the interphotoreceptor matrix of the retina between the retinal pigment epithelium and the photoreceptor cells. It is thought to transport retinoids between the retinal pigment epithelium and the photoreceptors, a critical role in the visual process.The human IRBP gene is approximately 9.5 kbp in length and consists of four exons separated by three introns. The introns are 1.6-1.9 kbp long. The gene is transcribed by photoreceptor and retinoblastoma cells into an approximately 4.3-kilobase mRNA that is translated and processed into a glycosylated protein of 135,000 Da. The amino acid sequence of human IRBP can be divided into four contiguous homology domains with 33-38% identity, suggesting a series of gene duplication events. In the gene, the boundaries of these domains are not defined by exon-intron junctions, as might have been expected. The first three homology domains and part of the fourth are all encoded by the first large exon, which is 3,180 base pairs long. The remainder of the fourth domain is encoded in the last three exons, which are 191, 143, and approximately 740 base pairs long, respectively. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014441848).
• BP6: Variant 10-47351134-G-A is Benign according to our data. Variant chr10-47351134-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-47351134-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00316 (481/152392) while in subpopulation EAS AF= 0.0477 (247/5182). AF 95% confidence interval is 0.0428. There are 12 homozygotes in gnomad4. There are 280 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBP3	NM_002900.3	c.2650G>A	p.Val884Met	missense_variant	1/4	ENST00000584701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBP3	ENST00000584701.2	c.2650G>A	p.Val884Met	missense_variant	1/4	1	NM_002900.3	P1

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152274 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0477

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00470

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00678 AC: 1689 AN: 249218 Hom.: 26 AF XY: 0.00617 AC XY: 836 AN XY: 135386

Gnomad AFR exome AF: 0.000313

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.0440

Gnomad SAS exome AF: 0.00222

Gnomad FIN exome AF: 0.00852

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00221 AC: 3228 AN: 1460650 Hom.: 37 Cov.: 34 AF XY: 0.00218 AC XY: 1581 AN XY: 726632

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0332

Gnomad4 SAS exome AF: 0.00283

Gnomad4 FIN exome AF: 0.00699

Gnomad4 NFE exome AF: 0.000341

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152392 Hom.: 12 Cov.: 33 AF XY: 0.00376 AC XY: 280 AN XY: 74528

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0477

Gnomad4 SAS AF: 0.00434

Gnomad4 FIN AF: 0.00470

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000875 Hom.: 1

Bravo AF: 0.00398

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 28, 2015

- -

Retinitis pigmentosa;C3715216:Retinitis pigmentosa 66 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.014	T
Sift4G	Uncertain	0.0040	D
Vest4		0.51
gMVP		0.92

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: rs11204213; hg19: chr10-48388228;