chr8-54626835-A-T

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.2953A>T(p.Asn985Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,613,258 control chromosomes in the GnomAD database, including 125,356 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9212 hom., cov: 32)

Exomes 𝑓: 0.39 ( 116144 hom. )

Consequence

RP1
NM_006269.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.80

Publications

47 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=8.9737773E-4).

BP6

Variant 8-54626835-A-T is Benign according to our data. Variant chr8-54626835-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006269.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1	NM_006269.2	MANE Select	c.2953A>T	p.Asn985Tyr	missense	Exon 4 of 4	NP_006260.1
	RP1	NM_001375654.1		c.787+4547A>T		intron	N/A	NP_001362583.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RP1	ENST00000220676.2	TSL:1 MANE Select	c.2953A>T	p.Asn985Tyr	missense	Exon 4 of 4	ENSP00000220676.1
RP1	ENST00000637698.1	TSL:5	c.787+4547A>T		intron	N/A	ENSP00000490104.1
RP1	ENST00000636932.1	TSL:5	c.787+4547A>T		intron	N/A	ENSP00000489857.1

Frequencies

GnomAD3 genomes

AF:

0.332

AC:

50429

AN:

151910

Hom.:

9206

Cov.:

show subpopulations

Gnomad AFR

AF:

0.217

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.537

Gnomad EAS

AF:

0.0666

Gnomad SAS

AF:

0.341

Gnomad FIN

AF:

0.400

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.363

GnomAD2 exomes

AF:

0.343

AC:

86181

AN:

251018

AF XY:

0.356

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.198

Gnomad ASJ exome

AF:

0.529

Gnomad EAS exome

AF:

0.0606

Gnomad FIN exome

AF:

0.412

Gnomad NFE exome

AF:

0.418

Gnomad OTH exome

AF:

0.399

GnomAD4 exome

AF:

0.390

AC:

570231

AN:

1461230

Hom.:

116144

Cov.:

AF XY:

0.391

AC XY:

284389

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.214

AC:

7167

AN:

33480

American (AMR)

AF:

0.211

AC:

9447

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

13790

AN:

26128

East Asian (EAS)

AF:

0.0866

AC:

3437

AN:

39684

South Asian (SAS)

AF:

0.344

AC:

29684

AN:

86248

European-Finnish (FIN)

AF:

0.407

AC:

21624

AN:

53132

Middle Eastern (MID)

AF:

0.470

AC:

2710

AN:

5766

European-Non Finnish (NFE)

AF:

0.413

AC:

459305

AN:

1111680

Other (OTH)

AF:

0.382

AC:

23067

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

20783

41565

62348

83130

103913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13762

27524

41286

55048

68810

<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:

0.332

AC:

50443

AN:

152028

Hom.:

9212

Cov.:

AF XY:

0.329

AC XY:

24428

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.216

AC:

8972

AN:

41484

American (AMR)

AF:

0.270

AC:

4128

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

1862

AN:

3470

East Asian (EAS)

AF:

0.0667

AC:

345

AN:

5170

South Asian (SAS)

AF:

0.343

AC:

1653

AN:

4814

European-Finnish (FIN)

AF:

0.400

AC:

4223

AN:

10556

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.413

AC:

28049

AN:

67934

Other (OTH)

AF:

0.358

AC:

755

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1651

3302

4952

6603

8254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.390

Hom.:

9046

Bravo

AF:

0.317

TwinsUK

AF:

0.424

AC:

1571

ALSPAC

AF:

0.409

AC:

1576

ESP6500AA

AF:

0.214

AC:

944

ESP6500EA

AF:

0.417

AC:

3584

ExAC

AF:

0.347

AC:

42142

Asia WGS

AF:

0.192

AC:

668

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 02, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32141364, 12764676)

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:2

Oct 02, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

Hypertriglyceridemia 1

Benign:1

Jul 15, 2010

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

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

Mar 06, 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.47

MetaRNN

Benign

0.00090

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

PhyloP100

1.8

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.075

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.98

Vest4

0.11

MPC

0.19

ClinPred

0.027

GERP RS

1.9

Varity_R

0.26

gMVP

0.29

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over