NM_002900.3:c.1037G>A

Variant names:

• chr10-47349521-G-A
• rs111245635
• NM_002900.3:c.1037G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_002900.3(RBP3):​c.1037G>A​(p.Arg346His) variant causes a missense change. The variant allele was found at a frequency of 0.0122 in 1,612,944 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R346C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0076 (7 hom., cov: 33)
  • Exomes 𝑓: 0.013 (140 hom.)
• Consequence: RBP3 NM_002900.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 4.25
• Publications: 13 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.085944325).
• BP6: Variant 10-47349521-G-A is Benign according to our data. Variant chr10-47349521-G-A is described in ClinVar as Benign. ClinVar VariationId is 208300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00762 (1160/152260) while in subpopulation NFE AF = 0.0137 (931/68008). AF 95% confidence interval is 0.013. There are 7 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1037G>A	p.Arg346His	missense	Exon 1 of 4	NP_002891.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBP3	ENST00000584701.2	TSL:1 MANE Select	c.1037G>A	p.Arg346His	missense	Exon 1 of 4	ENSP00000463151.1

Frequencies

GnomAD3 genomes AF: 0.00762 AC: 1160 AN: 152142 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00735 AC: 1830 AN: 248946 AF XY: 0.00752

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.000898

Gnomad EAS exome AF: 0.00109

Gnomad FIN exome AF: 0.00414

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00867

GnomAD4 exome AF: 0.0127 AC: 18578 AN: 1460684 Hom.: 140 Cov.: 34 AF XY: 0.0124 AC XY: 9001 AN XY: 726640

African (AFR) AF: 0.00260 AC: 87 AN: 33480

American (AMR) AF: 0.00505 AC: 226 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.00165 AC: 142 AN: 86258

European-Finnish (FIN) AF: 0.00498 AC: 260 AN: 52234

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0154 AC: 17084 AN: 1111996

Other (OTH) AF: 0.0122 AC: 737 AN: 60388

GnomAD4 genome AF: 0.00762 AC: 1160 AN: 152260 Hom.: 7 Cov.: 33 AF XY: 0.00709 AC XY: 528 AN XY: 74450

African (AFR) AF: 0.00231 AC: 96 AN: 41548

American (AMR) AF: 0.00523 AC: 80 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4816

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 931 AN: 68008

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.0125 Hom.: 23

Bravo AF: 0.00776

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Retinitis pigmentosa (1)
-	1	-	Retinitis pigmentosa 66 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.086	T
PhyloP100		4.3
Sift4G	Uncertain	0.0070	D
Vest4		0.66
gMVP		0.90

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: rs111245635; hg19: chr10-48389841;