8-54623810-G-A

Variant names:

• chr8-54623810-G-A
• rs428854
• NM_006269.2:c.788-860G>A

Variant summary

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

The NM_006269.2(RP1):​c.788-860G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,088 control chromosomes in the GnomAD database, including 4,268 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 0.22 (4268 hom., cov: 32)
• Consequence: RP1 NM_006269.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 2 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_006269.2	c.788-860G>A		intron_variant	Intron 3 of 3	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP1	ENST00000220676.2	c.788-860G>A		intron_variant	Intron 3 of 3	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1	c.787+1522G>A		intron_variant	Intron 3 of 28	5		ENSP00000490104.1
RP1	ENST00000636932.1	c.787+1522G>A		intron_variant	Intron 3 of 22	5		ENSP00000489857.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33465 AN: 151970 Hom.: 4259 Cov.: 32

Gnomad AFR AF: 0.0996

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.421

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.220 AC: 33498 AN: 152088 Hom.: 4268 Cov.: 32 AF XY: 0.221 AC XY: 16390 AN XY: 74330

African (AFR) AF: 0.100 AC: 4152 AN: 41510

American (AMR) AF: 0.319 AC: 4869 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3470

East Asian (EAS) AF: 0.421 AC: 2177 AN: 5174

South Asian (SAS) AF: 0.238 AC: 1144 AN: 4810

European-Finnish (FIN) AF: 0.206 AC: 2170 AN: 10554

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17390 AN: 67980

Other (OTH) AF: 0.254 AC: 536 AN: 2110

Alfa AF: 0.221 Hom.: 512

Bravo AF: 0.225

Asia WGS AF: 0.318 AC: 1106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.55
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs428854; hg19: chr8-55536370;