8-54628953-T-C

Variant names:

Variant summary

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

The NM_006269.2(RP1):c.5071T>C(p.Ser1691Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,824 control chromosomes in the GnomAD database, including 60,729 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 0.26 ( 5376 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55353 hom. )

Consequence

RP1
NM_006269.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0640

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=1.4066696E-4).

BP6

Variant 8-54628953-T-C is Benign according to our data. Variant chr8-54628953-T-C is described in ClinVar as [Benign]. Clinvar id is 95354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54628953-T-C is described in Lovd as [Benign].

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 link	c.5071T>C	p.Ser1691Pro	missense_variant	Exon 4 of 4	ENST00000220676.2	NP_006260.1	P56715

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RP1	ENST00000220676.2 link	c.5071T>C	p.Ser1691Pro	missense_variant	Exon 4 of 4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 link	c.787+6665T>C		intron_variant	Intron 3 of 28	5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 link	c.787+6665T>C		intron_variant	Intron 3 of 22	5		ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

39081

AN:

151890

Hom.:

5366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.227

Gnomad AMR

AF:

0.348

Gnomad ASJ

AF:

0.233

Gnomad EAS

AF:

0.421

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.214

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.272

Gnomad OTH

AF:

0.293

GnomAD3 exomes

AF:

0.277

AC:

69748

AN:

251360

Hom.:

10345

AF XY:

0.275

AC XY:

37337

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.329

Gnomad ASJ exome

AF:

0.234

Gnomad EAS exome

AF:

0.441

Gnomad SAS exome

AF:

0.241

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.275

Gnomad OTH exome

AF:

0.278

GnomAD4 exome

AF:

0.272

AC:

397874

AN:

1461818

Hom.:

55353

Cov.:

AF XY:

0.271

AC XY:

197185

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.193

Gnomad4 AMR exome

AF:

0.329

Gnomad4 ASJ exome

AF:

0.234

Gnomad4 EAS exome

AF:

0.405

Gnomad4 SAS exome

AF:

0.245

Gnomad4 FIN exome

AF:

0.215

Gnomad4 NFE exome

AF:

0.273

Gnomad4 OTH exome

AF:

0.273

GnomAD4 genome

AF:

0.257

AC:

39123

AN:

152006

Hom.:

5376

Cov.:

AF XY:

0.257

AC XY:

19090

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.348

Gnomad4 ASJ

AF:

0.233

Gnomad4 EAS

AF:

0.421

Gnomad4 SAS

AF:

0.245

Gnomad4 FIN

AF:

0.214

Gnomad4 NFE

AF:

0.272

Gnomad4 OTH

AF:

0.295

Alfa

AF:

0.268

Hom.:

9185

Bravo

AF:

0.265

TwinsUK

AF:

0.275

AC:

1018

ALSPAC

AF:

0.265

AC:

1020

ESP6500AA

AF:

0.200

AC:

883

ESP6500EA

AF:

0.272

AC:

2341

ExAC

AF:

0.272

AC:

33062

Asia WGS

AF:

0.331

AC:

1150

AN:

3478

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 13, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa 1

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Retinitis pigmentosa

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.057

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.018

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.19

MetaRNN

Benign

0.00014

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.20

PrimateAI

Benign

0.19

PROVEAN

Benign

0.37

REVEL

Benign

0.053

Sift

Benign

0.43

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.023

MPC

0.032

ClinPred

0.0024

GERP RS

3.7

Varity_R

0.085

gMVP

0.079

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