rs786205626

Variant names:

• chr15-89217168-TGAAGCGCAGGAA-T
• rs786205626
• NM_000326.5:c.286_297delTTCCTGCGCTTC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM4 PP3 PP5_Very_Strong

The NM_000326.5(RLBP1):​c.286_297delTTCCTGCGCTTC​(p.Phe96_Phe99del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F96F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RLBP1 NM_000326.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.62
• Publications: 1 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, Labcorp Genetics (formerly Invitae), G2P
• RLBP1-related retinopathy

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

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000326.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 15-89217168-TGAAGCGCAGGAA-T is Pathogenic according to our data. Variant chr15-89217168-TGAAGCGCAGGAA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 191289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 5 of 9	NP_000317.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLBP1	ENST00000268125.10	TSL:1 MANE Select	c.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 5 of 9	ENSP00000268125.5
	RLBP1	ENST00000873617.1		c.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 5 of 9	ENSP00000543676.1
	RLBP1	ENST00000873618.1		c.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 5 of 9	ENSP00000543677.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250780 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461762 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Bothnia retinal dystrophy (2)
2	-	-	not provided (2)
2	-	-	Retinal dystrophy (2)
1	-	-	Abnormality of the eye (1)
1	-	-	Autosomal recessive retinitis pigmentosa (1)
1	-	-	Retinitis pigmentosa (1)
1	-	-	Retinitis punctata albescens (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs786205626; hg19: chr15-89760399;