chr15-89210347-C-T

Variant names:

• chr15-89210347-C-T
• rs2051526502
• NM_000326.5:c.892G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000326.5(RLBP1):​c.892G>A​(p.Gly298Ser) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G298D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RLBP1 NM_000326.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-89210346-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RLBP1	NM_000326.5	c.892G>A	p.Gly298Ser	missense_variant	Exon 9 of 9	ENST00000268125.10	NP_000317.1
RLBP1	XM_011521870.3	c.892G>A	p.Gly298Ser	missense_variant	Exon 9 of 9		XP_011520172.1
RLBP1	XM_047432927.1	c.892G>A	p.Gly298Ser	missense_variant	Exon 7 of 7		XP_047288883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RLBP1	ENST00000268125.10	c.892G>A	p.Gly298Ser	missense_variant	Exon 9 of 9	1	NM_000326.5	ENSP00000268125.5
RLBP1	ENST00000563254.1	c.262G>A	p.Gly88Ser	missense_variant	Exon 3 of 3	2		ENSP00000454740.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 02, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RLBP1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 298 of the RLBP1 protein (p.Gly298Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.060	N
REVEL	Uncertain	0.54
Sift	Benign	0.70	T
Sift4G	Benign	0.50	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.45		Gain of ubiquitination at K295 (P = 0.0918);
MVP		0.85
MPC		0.69
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.89

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: rs2051526502; hg19: chr15-89753578;