rs35686775

chr10-47348971-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_002900.3(RBP3):c.487T>C(p.Ser163Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,894 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (9 hom.)
• Consequence: RBP3 NM_002900.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 3.06

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3336863).
• BP6: Variant 10-47348971-T-C is Benign according to our data. Variant chr10-47348971-T-C is described in ClinVar as [Benign]. Clinvar id is 208295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-47348971-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00571 (870/152242) while in subpopulation AFR AF= 0.0201 (837/41558). AF 95% confidence interval is 0.019. There are 10 homozygotes in gnomad4. There are 410 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBP3	NM_002900.3	c.487T>C	p.Ser163Pro	missense_variant	1/4	ENST00000584701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBP3	ENST00000584701.2	c.487T>C	p.Ser163Pro	missense_variant	1/4	1	NM_002900.3	P1

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 869 AN: 152124 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00144 AC: 363 AN: 251356 Hom.: 4 AF XY: 0.000942 AC XY: 128 AN XY: 135882

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000556 AC: 812 AN: 1461652 Hom.: 9 Cov.: 32 AF XY: 0.000451 AC XY: 328 AN XY: 727138

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00571 AC: 870 AN: 152242 Hom.: 10 Cov.: 33 AF XY: 0.00551 AC XY: 410 AN XY: 74436

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00249 Hom.: 1

Bravo AF: 0.00658

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 66 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Jun 27, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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	0.31
BayesDel_noAF	Benign	-0.16
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.33	T
Sift4G	Pathogenic	0.0010	D
Vest4		0.89
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: rs35686775; hg19: chr10-48390391;