NM_006269.2:c.1267_1656delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA

Variant names:

• chr8-54625149-GCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATT-A
• rs1554519422
• NM_006269.2:c.1267_1656delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_006269.2(RP1):​c.1267_1656delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA​(p.Ala423AsnfsTer11) variant causes a frameshift, missense change. 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A423A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RP1 NM_006269.2 frameshift, missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.58
• Publications: 1 publications found

Genes affected

RP1 (HGNC:10263): (RP1 axonemal microtubule associated) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains, which bind microtubules and regulate microtubule polymerization. The encoded protein is a photoreceptor microtubule-associated protein and is required for correct stacking of outer segment disc. This protein and the RP1L1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Because of its response to in vivo retinal oxygen levels, this protein was initially named ORP1 (oxygen-regulated protein-1). This protein was subsequently designated RP1 (retinitis pigmentosa 1) when it was found that mutations in this gene cause autosomal dominant retinitis pigmentosa. Mutations in this gene also cause autosomal recessive retinitis pigmentosa. Transcript variants resulted from an alternative promoter and alternative splicings have been found, which overlap the current reference sequence and has several exons upstream and downstream of the current reference sequence. However, the biological validity and full-length nature of some variants cannot be determined at this time.[provided by RefSeq, Sep 2010]

RP1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Illumina
• RP1-related dominant retinopathy

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• RP1-related recessive retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 254 pathogenic variants in the truncated region.
• PP5: Variant 8-54625149-GCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATT-A is Pathogenic according to our data. Variant chr8-54625149-GCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547180.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006269.2. 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
	RP1	NM_006269.2	MANE Select	c.1267_1656delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA	p.Ala423AsnfsTer11	frameshift missense	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+2861_787+3250delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA		intron	N/A	NP_001362583.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1	ENST00000220676.2	TSL:1 MANE Select	c.1267_1656delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA	p.Ala423AsnfsTer11	frameshift missense	Exon 4 of 4	ENSP00000220676.1	P56715
	RP1	ENST00000637698.1	TSL:5	c.787+2861_787+3250delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
	RP1	ENST00000636932.1	TSL:5	c.787+2861_787+3250delGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATTinsA		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

Splicing

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

Other links and lift over

dbSNP: rs1554519422; hg19: chr8-55537709;