rs444772

Positions:

chr8-54626497-G-A

Variant summary

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

The NM_006269.2(RP1):c.2615G>A(p.Arg872His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,004 control chromosomes in the GnomAD database, including 60,244 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 0.25 ( 5112 hom., cov: 31)

Exomes 𝑓: 0.27 ( 55132 hom. )

Consequence

RP1
NM_006269.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.78

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=0.0014749765).

BP6

Variant 8-54626497-G-A is Benign according to our data. Variant chr8-54626497-G-A is described in ClinVar as [Benign]. Clinvar id is 167602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54626497-G-A is described in Lovd as [Benign]. Variant chr8-54626497-G-A is described in Lovd as [Likely_pathogenic].

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/exons	MANE	Protein	UniProt
RP1	NM_006269.2 linkuse as main transcript	c.2615G>A	p.Arg872His	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.2615G>A	p.Arg872His	missense_variant	4/4	1	NM_006269.2	ENSP00000220676
RP1	ENST00000636932.1 linkuse as main transcript	c.787+4209G>A		intron_variant		5		ENSP00000489857
RP1	ENST00000637698.1 linkuse as main transcript	c.787+4209G>A		intron_variant		5		ENSP00000490104	P1

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37833

AN:

151512

Hom.:

5104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.227

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.421

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.214

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.272

Gnomad OTH

AF:

0.285

GnomAD3 exomes

AF:

0.276

AC:

68980

AN:

249880

Hom.:

10228

AF XY:

0.274

AC XY:

37086

AN XY:

135554

show subpopulations

Gnomad AFR exome

AF:

0.159

Gnomad AMR exome

AF:

0.328

Gnomad ASJ exome

AF:

0.234

Gnomad EAS exome

AF:

0.441

Gnomad SAS exome

AF:

0.244

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.278

GnomAD4 exome

AF:

0.271

AC:

396612

AN:

1461374

Hom.:

55132

Cov.:

AF XY:

0.271

AC XY:

196707

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.164

Gnomad4 AMR exome

AF:

0.328

Gnomad4 ASJ exome

AF:

0.234

Gnomad4 EAS exome

AF:

0.405

Gnomad4 SAS exome

AF:

0.247

Gnomad4 FIN exome

AF:

0.215

Gnomad4 NFE exome

AF:

0.273

Gnomad4 OTH exome

AF:

0.271

GnomAD4 genome

AF:

0.250

AC:

37868

AN:

151630

Hom.:

5112

Cov.:

AF XY:

0.249

AC XY:

18473

AN XY:

74066

show subpopulations

Gnomad4 AFR

AF:

0.166

Gnomad4 AMR

AF:

0.345

Gnomad4 ASJ

AF:

0.234

Gnomad4 EAS

AF:

0.421

Gnomad4 SAS

AF:

0.247

Gnomad4 FIN

AF:

0.214

Gnomad4 NFE

AF:

0.272

Gnomad4 OTH

AF:

0.287

Alfa

AF:

0.279

Hom.:

14601

Bravo

AF:

0.256

TwinsUK

AF:

0.274

AC:

1017

ALSPAC

AF:

0.265

AC:

1020

ESP6500AA

AF:

0.169

AC:

743

ESP6500EA

AF:

0.271

AC:

2330

ExAC

AF:

0.270

AC:

32708

Asia WGS

AF:

0.326

AC:

1133

AN:

3474

EpiCase

AF:

0.280

EpiControl

AF:

0.278

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 21, 2014	- -
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	-	- -

not provided

Benign:2

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	-	- -

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 13, 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

0.099

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.11

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.44

REVEL

Benign

0.079

Sift

Benign

0.031

Sift4G

Uncertain

0.047

Polyphen

0.24

Vest4

0.042

MPC

0.062

ClinPred

0.015

GERP RS

1.4

Varity_R

0.038

gMVP

0.092

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