rs446227

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000220676.2(RP1):c.5008G>A(p.Ala1670Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,613,814 control chromosomes in the GnomAD database, including 53,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4272 hom., cov: 32)

Exomes 𝑓: 0.26 ( 49563 hom. )

Consequence

RP1
ENST00000220676.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:10

Conservation

PhyloP100: -0.0880

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7616153E-4).

BP6

Variant 8-54628890-G-A is Benign according to our data. Variant chr8-54628890-G-A is described in ClinVar as [Benign]. Clinvar id is 95352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54628890-G-A is described in Lovd as [Benign]. Variant chr8-54628890-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1	NM_006269.2 linkuse as main transcript	c.5008G>A	p.Ala1670Thr	missense_variant	4/4	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RP1	ENST00000220676.2 linkuse as main transcript	c.5008G>A	p.Ala1670Thr	missense_variant	4/4	1	NM_006269.2	ENSP00000220676
RP1	ENST00000636932.1 linkuse as main transcript	c.787+6602G>A		intron_variant		5		ENSP00000489857
RP1	ENST00000637698.1 linkuse as main transcript	c.787+6602G>A		intron_variant		5		ENSP00000490104	P1

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33457

AN:

151910

Hom.:

4263

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0996

Gnomad AMI

AF:

0.214

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.420

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.252

GnomAD3 exomes

AF:

0.259

AC:

65151

AN:

251166

Hom.:

9280

AF XY:

0.258

AC XY:

35014

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0953

Gnomad AMR exome

AF:

0.314

Gnomad ASJ exome

AF:

0.227

Gnomad EAS exome

AF:

0.441

Gnomad SAS exome

AF:

0.234

Gnomad FIN exome

AF:

0.199

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.256

AC:

374369

AN:

1461786

Hom.:

49563

Cov.:

AF XY:

0.256

AC XY:

185803

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0974

Gnomad4 AMR exome

AF:

0.312

Gnomad4 ASJ exome

AF:

0.229

Gnomad4 EAS exome

AF:

0.405

Gnomad4 SAS exome

AF:

0.237

Gnomad4 FIN exome

AF:

0.204

Gnomad4 NFE exome

AF:

0.258

Gnomad4 OTH exome

AF:

0.254

GnomAD4 genome

AF:

0.220

AC:

33490

AN:

152028

Hom.:

4272

Cov.:

AF XY:

0.220

AC XY:

16381

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.100

Gnomad4 AMR

AF:

0.319

Gnomad4 ASJ

AF:

0.229

Gnomad4 EAS

AF:

0.420

Gnomad4 SAS

AF:

0.237

Gnomad4 FIN

AF:

0.205

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.254

Alfa

AF:

0.259

Hom.:

13050

Bravo

AF:

0.225

TwinsUK

AF:

0.259

AC:

960

ALSPAC

AF:

0.253

AC:

975

ESP6500AA

AF:

0.108

AC:

474

ESP6500EA

AF:

0.256

AC:

2199

ExAC

AF:

0.253

AC:

30695

Asia WGS

AF:

0.319

AC:

1109

AN:

3478

EpiCase

AF:

0.262

EpiControl

AF:

0.260

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Oct 26, 2012

- -

Retinitis pigmentosa 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.39

DANN

Benign

0.59

DEOGEN2

Benign

0.025

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.42

MetaRNN

Benign

0.00018

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.14

REVEL

Benign

0.018

Sift

Benign

0.57

Sift4G

Benign

1.0

Polyphen

0.011

Vest4

0.013

MPC

0.029

ClinPred

0.0032

GERP RS

-0.33

Varity_R

0.043

gMVP

0.066

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over