rs112888313

Positions:

• chr10-47350561-G-A
• chr10-47350561-G-C
• chr10-47350561-G-T

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.2077G>A​(p.Val693Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,612,946 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (24 hom.)
• Consequence: RBP3 NM_002900.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 2.87

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=0.0078342855).
• BP6: Variant 10-47350561-G-A is Benign according to our data. Variant chr10-47350561-G-A is described in ClinVar as [Benign]. Clinvar id is 208314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-47350561-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00794 (1209/152298) while in subpopulation AFR AF= 0.0269 (1118/41558). AF 95% confidence interval is 0.0256. There are 16 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBP3	NM_002900.3	c.2077G>A	p.Val693Met	missense_variant	1/4	ENST00000584701.2	NP_002891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBP3	ENST00000584701.2	c.2077G>A	p.Val693Met	missense_variant	1/4	1	NM_002900.3	ENSP00000463151	P1

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 1199 AN: 152180 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00231 AC: 575 AN: 248562 Hom.: 11 AF XY: 0.00165 AC XY: 223 AN XY: 135218

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.00104 AC: 1519 AN: 1460648 Hom.: 24 Cov.: 34 AF XY: 0.000874 AC XY: 635 AN XY: 726626

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00794 AC: 1209 AN: 152298 Hom.: 16 Cov.: 33 AF XY: 0.00753 AC XY: 561 AN XY: 74458

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00140 Hom.: 2

Bravo AF: 0.00952

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinitis pigmentosa 66 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Jun 27, 2013

- -

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	0.074
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0078	T
Sift4G	Benign	0.39	T
Vest4		0.045
gMVP		0.76

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: rs112888313; hg19: chr10-48388801;