8-54628666-G-A

Position:

chr8-54628666-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.4784G>A(p.Arg1595Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,613,912 control chromosomes in the GnomAD database, including 388 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 0.030 ( 134 hom., cov: 32)

Exomes 𝑓: 0.015 ( 254 hom. )

Consequence

RP1
NM_006269.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.83

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=0.003299117).

BP6

Variant 8-54628666-G-A is Benign according to our data. Variant chr8-54628666-G-A is described in ClinVar as [Benign]. Clinvar id is 363303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54628666-G-A is described in Lovd as [Benign]. Variant chr8-54628666-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1	NM_006269.2 link	c.4784G>A	p.Arg1595Gln	missense_variant	4/4	ENST00000220676.2	NP_006260.1	P56715

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RP1	ENST00000220676.2 link	c.4784G>A	p.Arg1595Gln	missense_variant	4/4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 link	c.787+6378G>A		intron_variant		5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 link	c.787+6378G>A		intron_variant		5		ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4582

AN:

152004

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0688

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0264

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.00841

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.0330

GnomAD3 exomes

AF:

0.0164

AC:

4119

AN:

251182

Hom.:

AF XY:

0.0157

AC XY:

2137

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.0675

Gnomad AMR exome

AF:

0.0148

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00693

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0154

AC:

22466

AN:

1461790

Hom.:

254

Cov.:

AF XY:

0.0151

AC XY:

10958

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0699

Gnomad4 AMR exome

AF:

0.0159

Gnomad4 ASJ exome

AF:

0.00570

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.00735

Gnomad4 FIN exome

AF:

0.0113

Gnomad4 NFE exome

AF:

0.0151

Gnomad4 OTH exome

AF:

0.0177

GnomAD4 genome

AF:

0.0301

AC:

4585

AN:

152122

Hom.:

134

Cov.:

AF XY:

0.0297

AC XY:

2206

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0687

Gnomad4 AMR

AF:

0.0263

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00830

Gnomad4 FIN

AF:

0.00841

Gnomad4 NFE

AF:

0.0160

Gnomad4 OTH

AF:

0.0327

Alfa

AF:

0.0178

Hom.:

Bravo

AF:

0.0328

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0117

AC:

ESP6500AA

AF:

0.0672

AC:

296

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0173

AC:

2103

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0181

EpiControl

AF:

0.0182

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Retinitis pigmentosa 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Retinitis pigmentosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.25

PROVEAN

Benign

-2.0

REVEL

Benign

0.20

Sift

Uncertain

0.0020

Sift4G

Benign

0.097

Polyphen

0.99

Vest4

0.089

MPC

0.21

ClinPred

0.074

GERP RS

3.0

Varity_R

0.11

gMVP

0.25

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