ENST00000646684.1:n.128-7732A>G

Variant names:

• chr8-54524964-A-G
• rs9298506
• ENST00000646684.1:n.128-7732A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000646684.1(RP1):​n.128-7732A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 152,188 control chromosomes in the GnomAD database, including 2,664 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (2664 hom., cov: 33)
• Consequence: RP1 ENST00000646684.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810
• Publications: 61 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):

• RP1-related dominant retinopathy

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• retinitis pigmentosa 1

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1	ENST00000646684.1	n.128-7732A>G		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28342 AN: 152070 Hom.: 2664 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.178

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

GnomAD4 genome AF: 0.186 AC: 28372 AN: 152188 Hom.: 2664 Cov.: 33 AF XY: 0.188 AC XY: 13991 AN XY: 74390

African (AFR) AF: 0.172 AC: 7127 AN: 41522

American (AMR) AF: 0.143 AC: 2184 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 529 AN: 3472

East Asian (EAS) AF: 0.211 AC: 1093 AN: 5182

South Asian (SAS) AF: 0.234 AC: 1131 AN: 4824

European-Finnish (FIN) AF: 0.241 AC: 2555 AN: 10588

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13240 AN: 67994

Other (OTH) AF: 0.179 AC: 378 AN: 2108

Alfa AF: 0.187 Hom.: 12292

Bravo AF: 0.176

Asia WGS AF: 0.269 AC: 937 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.5
DANN	Benign	0.70
PhyloP100		0.081

Splicing

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

Other links and lift over

dbSNP: rs9298506; hg19: chr8-55437524; COSMIC: COSV68701849;