rs77775126

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006269.2(RP1):c.1118C>T(p.Thr373Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,614,112 control chromosomes in the GnomAD database, including 219 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 0.010 ( 19 hom., cov: 32)

Exomes 𝑓: 0.013 ( 200 hom. )

Consequence

RP1
NM_006269.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 0.856

Publications

25 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, PanelApp Australia, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_006269.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04813701).

BP6

Variant 8-54625000-C-T is Benign according to our data. Variant chr8-54625000-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0105 (1593/152266) while in subpopulation SAS AF = 0.024 (116/4824). AF 95% confidence interval is 0.0205. There are 19 homozygotes in GnomAd4. There are 754 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AD,AR,SD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP1	NM_006269.2	MANE Select	c.1118C>T	p.Thr373Ile	missense	Exon 4 of 4	NP_006260.1	P56715
	RP1	NM_001375654.1		c.787+2712C>T		intron	N/A	NP_001362583.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RP1	ENST00000220676.2	TSL:1 MANE Select	c.1118C>T	p.Thr373Ile	missense	Exon 4 of 4	ENSP00000220676.1	P56715
RP1	ENST00000637698.1	TSL:5	c.787+2712C>T		intron	N/A	ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1	TSL:5	c.787+2712C>T		intron	N/A	ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1598

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0125

AC:

3153

AN:

251296

AF XY:

0.0139

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00342

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0135

AC:

19670

AN:

1461846

Hom.:

200

Cov.:

AF XY:

0.0139

AC XY:

10117

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

33480

American (AMR)

AF:

0.00731

AC:

327

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0197

AC:

515

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0254

AC:

2188

AN:

86250

European-Finnish (FIN)

AF:

0.00462

AC:

247

AN:

53410

Middle Eastern (MID)

AF:

0.0212

AC:

122

AN:

5768

European-Non Finnish (NFE)

AF:

0.0138

AC:

15374

AN:

1111996

Other (OTH)

AF:

0.0136

AC:

824

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1194

2389

3583

4778

5972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

560

1120

1680

2240

2800

<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:

0.0105

AC:

1593

AN:

152266

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

754

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41556

American (AMR)

AF:

0.00726

AC:

111

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0240

AC:

116

AN:

4824

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0156

AC:

1064

AN:

68012

Other (OTH)

AF:

0.0137

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

169

253

338

422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0134

Hom.:

Bravo

AF:

0.0102

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0173

EpiControl

AF:

0.0181

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Retinitis pigmentosa 1 (4)

not specified (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.3

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.086

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.47

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

0.86

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.9

REVEL

Benign

0.034

Sift

Uncertain

0.0020

Sift4G

Benign

0.072

Varity_R

0.12

gMVP

0.17

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over