8-54629057-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006269.2(RP1):c.5175A>G(p.Gln1725Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,962 control chromosomes in the GnomAD database, including 53,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4156 hom., cov: 32)

Exomes 𝑓: 0.26 ( 49393 hom. )

Consequence

RP1
NM_006269.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.663

Publications

28 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 8-54629057-A-G is Benign according to our data. Variant chr8-54629057-A-G is described in ClinVar as Benign. ClinVar VariationId is 95355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.663 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_006269.2 link	c.5175A>G	p.Gln1725Gln	synonymous_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.5175A>G	p.Gln1725Gln	synonymous_variant	Exon 4 of 4	1	NM_006269.2	ENSP00000220676.1
RP1	ENST00000637698.1 link	c.787+6769A>G		intron_variant	Intron 3 of 28	5		ENSP00000490104.1
RP1	ENST00000636932.1 link	c.787+6769A>G		intron_variant	Intron 3 of 22	5		ENSP00000489857.1

Frequencies

GnomAD3 genomes

AF:

0.214

AC:

32558

AN:

152056

Hom.:

4148

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0803

Gnomad AMI

AF:

0.214

Gnomad AMR

AF:

0.312

Gnomad ASJ

AF:

0.229

Gnomad EAS

AF:

0.422

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.205

Gnomad MID

AF:

0.268

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.246

GnomAD2 exomes

AF:

0.258

AC:

64790

AN:

251318

AF XY:

0.257

show subpopulations

Gnomad AFR exome

AF:

0.0757

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.228

Gnomad EAS exome

AF:

0.441

Gnomad FIN exome

AF:

0.199

Gnomad NFE exome

AF:

0.258

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.255

AC:

373326

AN:

1461788

Hom.:

49393

Cov.:

AF XY:

0.255

AC XY:

185330

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0769

AC:

2573

AN:

33478

American (AMR)

AF:

0.310

AC:

13864

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

5975

AN:

26132

East Asian (EAS)

AF:

0.405

AC:

16092

AN:

39698

South Asian (SAS)

AF:

0.237

AC:

20460

AN:

86256

European-Finnish (FIN)

AF:

0.204

AC:

10898

AN:

53414

Middle Eastern (MID)

AF:

0.263

AC:

1515

AN:

5768

European-Non Finnish (NFE)

AF:

0.258

AC:

286751

AN:

1111928

Other (OTH)

AF:

0.252

AC:

15198

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

18280

36560

54840

73120

91400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9730

19460

29190

38920

48650

<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:

0.214

AC:

32589

AN:

152174

Hom.:

4156

Cov.:

AF XY:

0.214

AC XY:

15933

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0808

AC:

3354

AN:

41532

American (AMR)

AF:

0.312

AC:

4770

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

794

AN:

3472

East Asian (EAS)

AF:

0.422

AC:

2182

AN:

5174

South Asian (SAS)

AF:

0.237

AC:

1142

AN:

4816

European-Finnish (FIN)

AF:

0.205

AC:

2171

AN:

10600

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.256

AC:

17383

AN:

67984

Other (OTH)

AF:

0.249

AC:

526

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1243

2487

3730

4974

6217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

352

704

1056

1408

1760

<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:

0.248

Hom.:

7803

Bravo

AF:

0.217

Asia WGS

AF:

0.317

AC:

1102

AN:

3478

EpiCase

AF:

0.262

EpiControl

AF:

0.260

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

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:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 13, 2019

GeneDx

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 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

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.25

(source)

DANN

Benign

0.73

PhyloP100

0.66

Mutation Taster

=100/0

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