15-89211749-CA-TT

Variant names:

• chr15-89211749-CA-TT
• NM_000326.5:c.677_678delTGinsAA
• RLBP1 p.Met226Lys

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1_Very_Strong PP3

The NM_000326.5(RLBP1):​c.677_678delTGinsAA​(p.Met226Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M226L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RLBP1 NM_000326.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.93
• Publications: 0 publications found

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]

RLBP1 Gene-Disease associations (from GenCC):

• Bothnia retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• RLBP1-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• fundus albipunctatus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Newfoundland cone-rod dystrophy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis punctata albescens

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_000326.5 (RLBP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000326.5. 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
	RLBP1	NM_000326.5	MANE Select	c.677_678delTGinsAA	p.Met226Lys	missense	N/A	NP_000317.1	P12271

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLBP1	ENST00000268125.10	TSL:1 MANE Select	c.677_678delTGinsAA	p.Met226Lys	missense	N/A	ENSP00000268125.5	P12271
	RLBP1	ENST00000873617.1		c.677_678delTGinsAA	p.Met226Lys	missense	N/A	ENSP00000543676.1
	RLBP1	ENST00000873618.1		c.677_678delTGinsAA	p.Met226Lys	missense	N/A	ENSP00000543677.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-89754980;