chr8-54629057-A-G

Position:

chr8-54629057-A-G

Variant summary

Our verdict is Benign. Variant got -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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54629057-A-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
RP1	NM_006269.2 linkuse as main transcript	c.5175A>G	p.Gln1725Gln	synonymous_variant	4/4	ENST00000220676.2	NP_006260.1	P56715

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RP1	ENST00000220676.2 linkuse as main transcript	c.5175A>G	p.Gln1725Gln	synonymous_variant	4/4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 linkuse as main transcript	c.787+6769A>G		intron_variant		5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 linkuse as main transcript	c.787+6769A>G		intron_variant		5		ENSP00000489857.1	A0A1B0GTV9

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

GnomAD3 exomes

AF:

0.258

AC:

64790

AN:

251318

Hom.:

9229

AF XY:

0.257

AC XY:

34864

AN XY:

135822

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 SAS exome

AF:

0.234

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

Gnomad4 AFR exome

AF:

0.0769

Gnomad4 AMR exome

AF:

0.310

Gnomad4 ASJ exome

AF:

0.229

Gnomad4 EAS exome

AF:

0.405

Gnomad4 SAS exome

AF:

0.237

Gnomad4 FIN exome

AF:

0.204

Gnomad4 NFE exome

AF:

0.258

Gnomad4 OTH exome

AF:

0.252

GnomAD4 genome

AF:

0.214

AC:

32589

AN:

152174

Hom.:

4156

Cov.:

AF XY:

0.214

AC XY:

15933

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0808

Gnomad4 AMR

AF:

0.312

Gnomad4 ASJ

AF:

0.229

Gnomad4 EAS

AF:

0.422

Gnomad4 SAS

AF:

0.237

Gnomad4 FIN

AF:

0.205

Gnomad4 NFE

AF:

0.256

Gnomad4 OTH

AF:

0.249

Alfa

AF:

0.252

Hom.:

6431

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2013	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	- -
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

Genome-Nilou Lab

Nov 07, 2021

- -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa

Benign: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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.25

DANN

Benign

0.73

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