rs186571865

Positions:

chr8-54622111-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_006269.2(RP1):c.616-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,614,088 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 36 hom. )

Consequence

RP1
NM_006269.2 splice_region, intron

Scores

Splicing: ADA: 0.0002528

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 1.63

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00443 (674/152302) while in subpopulation AMR AF= 0.00713 (109/15298). AF 95% confidence interval is 0.00637. There are 5 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP1	NM_006269.2 linkuse as main transcript	c.616-6T>C		splice_region_variant, intron_variant		ENST00000220676.2	NP_006260.1	P56715

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
RP1	ENST00000220676.2 linkuse as main transcript	c.616-6T>C	splice_region_variant, intron_variant	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 linkuse as main transcript	c.616-6T>C	splice_region_variant, intron_variant	5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 linkuse as main transcript	c.616-6T>C	splice_region_variant, intron_variant	5		ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

AF:

0.00442

AC:

672

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00687

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00505

AC:

1269

AN:

251374

Hom.:

AF XY:

0.00481

AC XY:

654

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00735

Gnomad ASJ exome

AF:

0.00665

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.00747

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00625

AC:

9132

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

4366

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00771

Gnomad4 ASJ exome

AF:

0.00662

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00176

Gnomad4 NFE exome

AF:

0.00721

Gnomad4 OTH exome

AF:

0.00560

GnomAD4 genome

AF:

0.00443

AC:

674

AN:

152302

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00713

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00688

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00588

Hom.:

Bravo

AF:

0.00514

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00632

EpiControl

AF:

0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	RP1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Retinitis pigmentosa

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely pathogenic, flagged submission	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 19, 2014

- -

Retinitis pigmentosa 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

6.6

DANN

Benign

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.028

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.26

Position offset: 6

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