rs786205494

Positions:

• chr15-89210721-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000268125.10(RLBP1):​c.773T>G​(p.Leu258Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RLBP1 ENST00000268125.10 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.88

Genes affected

RLBP1 (HGNC:10024): (retinaldehyde binding protein 1) The protein encoded by this gene is a 36-kD water-soluble protein which carries 11-cis-retinaldehyde or 11-cis-retinal as physiologic ligands. It may be a functional component of the visual cycle. Mutations of this gene have been associated with severe rod-cone dystrophy, Bothnia dystrophy (nonsyndromic autosomal recessive retinitis pigmentosa) and retinitis punctata albescens. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain CRAL-TRIO (size 161) in uniprot entity RLBP1_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in ENST00000268125.10
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 15-89210721-A-C is Pathogenic according to our data. Variant chr15-89210721-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191063.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-89210721-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLBP1	NM_000326.5	c.773T>G	p.Leu258Trp	missense_variant	8/9	ENST00000268125.10	NP_000317.1
RLBP1	XM_011521870.3	c.773T>G	p.Leu258Trp	missense_variant	8/9		XP_011520172.1
RLBP1	XM_047432927.1	c.773T>G	p.Leu258Trp	missense_variant	6/7		XP_047288883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RLBP1	ENST00000268125.10	c.773T>G	p.Leu258Trp	missense_variant	8/9	1	NM_000326.5	ENSP00000268125	P1
RLBP1	ENST00000563254.1	c.146T>G	p.Leu49Trp	missense_variant	2/3	2		ENSP00000454740
RLBP1	ENST00000567787.1			downstream_gene_variant		5		ENSP00000457251

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.84		Gain of methylation at K259 (P = 0.0485);
MVP		0.92
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.94

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: rs786205494; hg19: chr15-89753952;