chr8-54626497-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R872C) has been classified as Uncertain significance.

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

Publications

46 publications found

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 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

RP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 167602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2615G>A	p.Arg872His	missense_variant	Exon 4 of 4	ENST00000220676.2	NP_006260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RP1	ENST00000220676.2 link	c.2615G>A	p.Arg872His	missense_variant	Exon 4 of 4	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1 link	c.787+4209G>A		intron_variant	Intron 3 of 28	5		ENSP00000490104.1
RP1	ENST00000636932.1 link	c.787+4209G>A		intron_variant	Intron 3 of 22	5		ENSP00000489857.1

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

GnomAD2 exomes

AF:

0.276

AC:

68980

AN:

249880

AF XY:

0.274

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 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

African (AFR)

AF:

0.164

AC:

5503

AN:

33472

American (AMR)

AF:

0.328

AC:

14660

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

6123

AN:

26126

East Asian (EAS)

AF:

0.405

AC:

16067

AN:

39662

South Asian (SAS)

AF:

0.247

AC:

21320

AN:

86246

European-Finnish (FIN)

AF:

0.215

AC:

11481

AN:

53354

Middle Eastern (MID)

AF:

0.304

AC:

1754

AN:

5764

European-Non Finnish (NFE)

AF:

0.273

AC:

303322

AN:

1111662

Other (OTH)

AF:

0.271

AC:

16382

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

16897

33794

50692

67589

84486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10202

20404

30606

40808

51010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.250

AC:

37868

AN:

151630

Hom.:

5112

Cov.:

AF XY:

0.249

AC XY:

18473

AN XY:

74066

show subpopulations

African (AFR)

AF:

0.166

AC:

6877

AN:

41392

American (AMR)

AF:

0.345

AC:

5249

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.234

AC:

809

AN:

3460

East Asian (EAS)

AF:

0.421

AC:

2146

AN:

5098

South Asian (SAS)

AF:

0.247

AC:

1190

AN:

4812

European-Finnish (FIN)

AF:

0.214

AC:

2234

AN:

10440

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.272

AC:

18465

AN:

67898

Other (OTH)

AF:

0.287

AC:

604

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1402

2805

4207

5610

7012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.273

Hom.:

20886

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

Feb 21, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 13, 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

0.099

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

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

PhyloP100

1.8

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

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over