8-54626835-A-T

Position:

chr8-54626835-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N985SP) has been classified as Likely pathogenic.

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

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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-54626834-TAA-TTCTCC is described in Lovd as [Likely_pathogenic].

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 [Likely_benign]. Clinvar id is 5969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54626835-A-T is described in Lovd as [Benign]. Variant chr8-54626835-A-T is described in Lovd as [Likely_benign]. Variant chr8-54626835-A-T is described in Lovd as [Likely_pathogenic]. Variant chr8-54626835-A-T is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 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.2953A>T	p.Asn985Tyr	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 linkuse as main transcript	c.2953A>T	p.Asn985Tyr	missense_variant	4/4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 linkuse as main transcript	c.787+4547A>T		intron_variant		5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 linkuse as main transcript	c.787+4547A>T		intron_variant		5		ENSP00000489857.1	A0A1B0GTV9

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

GnomAD3 exomes

AF:

0.343

AC:

86181

AN:

251018

Hom.:

16817

AF XY:

0.356

AC XY:

48299

AN XY:

135728

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 SAS exome

AF:

0.348

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

Gnomad4 AFR exome

AF:

0.214

Gnomad4 AMR exome

AF:

0.211

Gnomad4 ASJ exome

AF:

0.528

Gnomad4 EAS exome

AF:

0.0866

Gnomad4 SAS exome

AF:

0.344

Gnomad4 FIN exome

AF:

0.407

Gnomad4 NFE exome

AF:

0.413

Gnomad4 OTH exome

AF:

0.382

GnomAD4 genome

AF:

0.332

AC:

50443

AN:

152028

Hom.:

9212

Cov.:

AF XY:

0.329

AC XY:

24428

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.216

Gnomad4 AMR

AF:

0.270

Gnomad4 ASJ

AF:

0.537

Gnomad4 EAS

AF:

0.0667

Gnomad4 SAS

AF:

0.343

Gnomad4 FIN

AF:

0.400

Gnomad4 NFE

AF:

0.413

Gnomad4 OTH

AF:

0.358

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 02, 2020	This variant is associated with the following publications: (PMID: 32141364, 12764676) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2013	- -

Retinitis pigmentosa 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Hypertriglyceridemia 1

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jul 15, 2010

- -

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

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

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

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

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

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