14-21328625-G-C

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.3097G>C(p.Glu1033Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,602,658 control chromosomes in the GnomAD database, including 97,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6860 hom., cov: 31)

Exomes 𝑓: 0.34 ( 90153 hom. )

Consequence

RPGRIP1
NM_020366.4 missense, splice_region

Scores

Splicing: ADA: 0.00005508

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.30

Publications

36 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=0.00586462).

BP6

Variant 14-21328625-G-C is Benign according to our data. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in CliVar as Benign/Likely_benign. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 link	c.3097G>C	p.Glu1033Gln	missense_variant, splice_region_variant	Exon 19 of 25	ENST00000400017.7	NP_065099.3	Q96KN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7 link	c.3097G>C	p.Glu1033Gln	missense_variant, splice_region_variant	Exon 19 of 25	1	NM_020366.4	ENSP00000382895.2		Q96KN7-1

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40432

AN:

151866

Hom.:

6860

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0632

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.256

Gnomad EAS

AF:

0.398

Gnomad SAS

AF:

0.488

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.355

Gnomad OTH

AF:

0.285

GnomAD2 exomes

AF:

0.331

AC:

82392

AN:

248546

AF XY:

0.345

show subpopulations

Gnomad AFR exome

AF:

0.0595

Gnomad AMR exome

AF:

0.198

Gnomad ASJ exome

AF:

0.250

Gnomad EAS exome

AF:

0.413

Gnomad FIN exome

AF:

0.390

Gnomad NFE exome

AF:

0.351

Gnomad OTH exome

AF:

0.340

GnomAD4 exome

AF:

0.345

AC:

500377

AN:

1450672

Hom.:

90153

Cov.:

AF XY:

0.350

AC XY:

252797

AN XY:

722254

show subpopulations

African (AFR)

AF:

0.0516

AC:

1722

AN:

33352

American (AMR)

AF:

0.203

AC:

9090

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6599

AN:

26068

East Asian (EAS)

AF:

0.377

AC:

14952

AN:

39632

South Asian (SAS)

AF:

0.477

AC:

40998

AN:

85966

European-Finnish (FIN)

AF:

0.400

AC:

21326

AN:

53308

Middle Eastern (MID)

AF:

0.275

AC:

1554

AN:

5648

European-Non Finnish (NFE)

AF:

0.348

AC:

383930

AN:

1102012

Other (OTH)

AF:

0.337

AC:

20206

AN:

60004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

14598

29195

43793

58390

72988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12078

24156

36234

48312

60390

<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:

0.266

AC:

40431

AN:

151986

Hom.:

6860

Cov.:

AF XY:

0.272

AC XY:

20183

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.0631

AC:

2618

AN:

41512

American (AMR)

AF:

0.231

AC:

3519

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

887

AN:

3466

East Asian (EAS)

AF:

0.399

AC:

2059

AN:

5156

South Asian (SAS)

AF:

0.487

AC:

2345

AN:

4812

European-Finnish (FIN)

AF:

0.377

AC:

3970

AN:

10534

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.355

AC:

24156

AN:

67950

Other (OTH)

AF:

0.288

AC:

606

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1379

2757

4136

5514

6893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.337

Hom.:

7031

Bravo

AF:

0.240

TwinsUK

AF:

0.334

AC:

1239

ALSPAC

AF:

0.361

AC:

1393

ESP6500AA

AF:

0.0709

AC:

265

ESP6500EA

AF:

0.352

AC:

2888

ExAC

AF:

0.336

AC:

40626

Asia WGS

AF:

0.453

AC:

1573

AN:

3478

EpiCase

AF:

0.347

EpiControl

AF:

0.327

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

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

- -

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

- -

Oct 03, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy 13

Benign:2

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21857984, 16123401, 20079931) -

Leber congenital amaurosis 6

Benign:2

Jan 13, 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

0.066

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.048

DEOGEN2

Benign

0.0012

T;T;T;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.61

T;T;T;T;T

MetaRNN

Benign

0.0059

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.94

.;.;N;.;.

PhyloP100

1.3

PrimateAI

Benign

0.35

PROVEAN

Benign

0.83

N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.99

T;T;T;T;T

Sift4G

Benign

0.59

T;T;T;T;T

Polyphen

0.0, 0.0010

.;.;B;B;B

Vest4

0.039

MPC

0.065

ClinPred

0.00094

GERP RS

1.8

PromoterAI

0.040

Neutral

(source)

Varity_R

0.049

gMVP

0.27

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.018

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