rs6571751

Variant names:

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.574A>G(p.Lys192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,561,794 control chromosomes in the GnomAD database, including 196,657 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 0.49 ( 18322 hom., cov: 32)

Exomes 𝑓: 0.50 ( 178335 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 1.43

Publications

41 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=2.9413291E-5).

BP6

Variant 14-21302571-A-G is Benign according to our data. Variant chr14-21302571-A-G is described in ClinVar as Benign. ClinVar VariationId is 99827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 link	c.574A>G	p.Lys192Glu	missense_variant	Exon 5 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.574A>G	p.Lys192Glu	missense_variant	Exon 5 of 25	1	NM_020366.4	ENSP00000382895.2	Q96KN7-1
RPGRIP1	ENST00000557771.5 link	c.574A>G	p.Lys192Glu	missense_variant	Exon 4 of 24	5		ENSP00000451219.1	G3V3F7
RPGRIP1	ENST00000556336.5 link	c.574A>G	p.Lys192Glu	missense_variant	Exon 4 of 21	5		ENSP00000450445.1	G3V236
RPGRIP1	ENST00000554750.1 link	n.173A>G		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.489

AC:

74340

AN:

151930

Hom.:

18303

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.481

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.321

Gnomad SAS

AF:

0.594

Gnomad FIN

AF:

0.524

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.509

Gnomad OTH

AF:

0.470

GnomAD2 exomes

AF:

0.503

AC:

100555

AN:

199846

AF XY:

0.508

show subpopulations

Gnomad AFR exome

AF:

0.454

Gnomad AMR exome

AF:

0.513

Gnomad ASJ exome

AF:

0.423

Gnomad EAS exome

AF:

0.327

Gnomad FIN exome

AF:

0.542

Gnomad NFE exome

AF:

0.507

Gnomad OTH exome

AF:

0.502

GnomAD4 exome

AF:

0.500

AC:

705005

AN:

1409746

Hom.:

178335

Cov.:

AF XY:

0.502

AC XY:

350608

AN XY:

697818

show subpopulations

African (AFR)

AF:

0.454

AC:

14736

AN:

32488

American (AMR)

AF:

0.510

AC:

19917

AN:

39084

Ashkenazi Jewish (ASJ)

AF:

0.416

AC:

10431

AN:

25050

East Asian (EAS)

AF:

0.307

AC:

11653

AN:

37994

South Asian (SAS)

AF:

0.594

AC:

46809

AN:

78758

European-Finnish (FIN)

AF:

0.544

AC:

27611

AN:

50764

Middle Eastern (MID)

AF:

0.507

AC:

2868

AN:

5658

European-Non Finnish (NFE)

AF:

0.502

AC:

542571

AN:

1081562

Other (OTH)

AF:

0.487

AC:

28409

AN:

58388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

14369

28738

43106

57475

71844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15926

31852

47778

63704

79630

<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:

0.489

AC:

74409

AN:

152048

Hom.:

18322

Cov.:

AF XY:

0.492

AC XY:

36536

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.461

AC:

19120

AN:

41460

American (AMR)

AF:

0.494

AC:

7535

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1493

AN:

3470

East Asian (EAS)

AF:

0.322

AC:

1662

AN:

5164

South Asian (SAS)

AF:

0.594

AC:

2868

AN:

4828

European-Finnish (FIN)

AF:

0.524

AC:

5535

AN:

10570

Middle Eastern (MID)

AF:

0.527

AC:

155

AN:

294

European-Non Finnish (NFE)

AF:

0.509

AC:

34610

AN:

67988

Other (OTH)

AF:

0.471

AC:

995

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1955

3910

5865

7820

9775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

678

1356

2034

2712

3390

<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:

0.496

Hom.:

95589

Bravo

AF:

0.478

TwinsUK

AF:

0.502

AC:

1863

ALSPAC

AF:

0.499

AC:

1923

ESP6500AA

AF:

0.448

AC:

1697

ESP6500EA

AF:

0.498

AC:

4112

ExAC

AF:

0.467

AC:

55358

Asia WGS

AF:

0.507

AC:

1763

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cone-rod dystrophy 13

Benign:2

Jan 12, 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. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 6

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2021

Genome-Nilou Lab

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.9

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.0019

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.24

T;T;T

MetaRNN

Benign

0.000029

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.28

.;.;N

PhyloP100

1.4

PrimateAI

Benign

0.33

PROVEAN

Benign

1.4

N;N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.12

MPC

0.091

ClinPred

0.0022

GERP RS

3.1

Varity_R

0.058

gMVP

0.13

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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