rs1040904

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020366.4(RPGRIP1):c.287C>A(p.Pro96Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 1,612,406 control chromosomes in the GnomAD database, including 3,144 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.057 ( 370 hom., cov: 31)

Exomes 𝑓: 0.048 ( 2774 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.480

Publications

17 publications found

Variant links:

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

RPGRIP1 Gene-Disease associations (from GenCC):

cone-rod dystrophy 13
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Leber congenital amaurosis 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RPGRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0026779473).

BP6

Variant 14-21301034-C-A is Benign according to our data. Variant chr14-21301034-C-A is described in ClinVar as Benign. ClinVar VariationId is 99819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 link	c.287C>A	p.Pro96Gln	missense_variant	Exon 4 of 25	ENST00000400017.7	NP_065099.3	Q96KN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPGRIP1	ENST00000400017.7 link	c.287C>A	p.Pro96Gln	missense_variant	Exon 4 of 25	1	NM_020366.4	ENSP00000382895.2	Q96KN7-1
RPGRIP1	ENST00000557771.5 link	c.287C>A	p.Pro96Gln	missense_variant	Exon 3 of 24	5		ENSP00000451219.1	G3V3F7
RPGRIP1	ENST00000556336.5 link	c.287C>A	p.Pro96Gln	missense_variant	Exon 3 of 21	5		ENSP00000450445.1	G3V236
RPGRIP1	ENST00000554750.1 link	n.-115C>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0570

AC:

8677

AN:

152180

Hom.:

363

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0562

Gnomad AMI

AF:

0.120

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.0608

Gnomad EAS

AF:

0.0349

Gnomad SAS

AF:

0.0339

Gnomad FIN

AF:

0.0272

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0420

Gnomad OTH

AF:

0.0459

GnomAD2 exomes

AF:

0.0709

AC:

17194

AN:

242586

AF XY:

0.0627

show subpopulations

Gnomad AFR exome

AF:

0.0522

Gnomad AMR exome

AF:

0.252

Gnomad ASJ exome

AF:

0.0581

Gnomad EAS exome

AF:

0.0355

Gnomad FIN exome

AF:

0.0283

Gnomad NFE exome

AF:

0.0419

Gnomad OTH exome

AF:

0.0609

GnomAD4 exome

AF:

0.0481

AC:

70169

AN:

1460108

Hom.:

2774

Cov.:

AF XY:

0.0468

AC XY:

33975

AN XY:

726328

show subpopulations

African (AFR)

AF:

0.0531

AC:

1774

AN:

33440

American (AMR)

AF:

0.239

AC:

10665

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.0561

AC:

1462

AN:

26078

East Asian (EAS)

AF:

0.0296

AC:

1173

AN:

39676

South Asian (SAS)

AF:

0.0348

AC:

3001

AN:

86224

European-Finnish (FIN)

AF:

0.0272

AC:

1431

AN:

52656

Middle Eastern (MID)

AF:

0.0689

AC:

397

AN:

5762

European-Non Finnish (NFE)

AF:

0.0427

AC:

47453

AN:

1111310

Other (OTH)

AF:

0.0466

AC:

2813

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

3951

7901

11852

15802

19753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1940

3880

5820

7760

9700

<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:

0.0572

AC:

8706

AN:

152298

Hom.:

370

Cov.:

AF XY:

0.0574

AC XY:

4276

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0565

AC:

2347

AN:

41558

American (AMR)

AF:

0.159

AC:

2429

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0608

AC:

211

AN:

3472

East Asian (EAS)

AF:

0.0350

AC:

181

AN:

5178

South Asian (SAS)

AF:

0.0337

AC:

163

AN:

4832

European-Finnish (FIN)

AF:

0.0272

AC:

289

AN:

10622

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0420

AC:

2858

AN:

68026

Other (OTH)

AF:

0.0454

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

399

797

1196

1594

1993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0453

Hom.:

277

Bravo

AF:

0.0686

TwinsUK

AF:

0.0472

AC:

175

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.0535

AC:

204

ESP6500EA

AF:

0.0390

AC:

317

ExAC

AF:

0.0604

AC:

7254

Asia WGS

AF:

0.0460

AC:

162

AN:

3478

EpiCase

AF:

0.0419

EpiControl

AF:

0.0485

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy 13

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Leber congenital amaurosis 6

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.0

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0023

T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.42

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.76

.;.;N

PhyloP100

0.48

PrimateAI

Benign

0.40

PROVEAN

Benign

2.0

N;N;N

REVEL

Benign

0.068

Sift

Benign

0.96

T;T;T

Sift4G

Benign

0.64

T;T;T

Polyphen

0.0070

.;.;B

Vest4

0.088

MPC

0.062

ClinPred

0.00052

GERP RS

-0.43

Varity_R

0.025

gMVP

0.068

Mutation Taster

=100/0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over