rs41284962

Variant names:

• chr10-47350115-G-A
• rs41284962
• NM_002900.3:c.1631G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-47350115-G-A
• chr10-47350115-G-C
• chr10-47350115-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002900.3(RBP3):​c.1631G>A​(p.Arg544His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,612,976 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R544C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (14 hom.)
• Consequence: RBP3 NM_002900.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.96
• Publications: 9 publications found

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]

RBP3 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 66

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077555478).
• BP6: Variant 10-47350115-G-A is Benign according to our data. Variant chr10-47350115-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94087.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0028 (426/152324) while in subpopulation NFE AF = 0.00507 (345/68020). AF 95% confidence interval is 0.00463. There are 1 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002900.3. 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
	RBP3	NM_002900.3	MANE Select	c.1631G>A	p.Arg544His	missense	Exon 1 of 4	NP_002891.1	P10745

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBP3	ENST00000584701.2	TSL:1 MANE Select	c.1631G>A	p.Arg544His	missense	Exon 1 of 4	ENSP00000463151.1	P10745

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152206 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00507

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00228 AC: 569 AN: 249172 AF XY: 0.00212

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000420

Gnomad NFE exome AF: 0.00451

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00472 AC: 6897 AN: 1460652 Hom.: 14 Cov.: 34 AF XY: 0.00458 AC XY: 3330 AN XY: 726668

African (AFR) AF: 0.000926 AC: 31 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.000516 AC: 27 AN: 52282

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00595 AC: 6621 AN: 1111970

Other (OTH) AF: 0.00301 AC: 182 AN: 60374

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152324 Hom.: 1 Cov.: 33 AF XY: 0.00266 AC XY: 198 AN XY: 74482

African (AFR) AF: 0.00101 AC: 42 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00507 AC: 345 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00364 Hom.: 2

Bravo AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	RBP3-related disorder (1)
-	1	-	Retinitis pigmentosa (1)
-	1	-	Retinitis pigmentosa 66 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0078	T
PhyloP100		2.0
Sift4G	Benign	0.27	T
Vest4		0.091
gMVP		0.81

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: rs41284962; hg19: chr10-48389247;