chr14-21325077-G-A

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.2215+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,599,062 control chromosomes in the GnomAD database, including 38,971 homozygotes. In-silico tool predicts 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 Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3235 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35736 hom. )

Consequence

RPGRIP1
NM_020366.4 splice_region, intron

Scores

Splicing: ADA: 0.00001395

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.875

Publications

12 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 (BayesDel_noAF=-0.84).

BP6

Variant 14-21325077-G-A is Benign according to our data. Variant chr14-21325077-G-A is described in ClinVar as Benign. ClinVar VariationId is 261227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 link	c.2215+7G>A		splice_region_variant, intron_variant	Intron 15 of 24	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.2215+7G>A		splice_region_variant, intron_variant	Intron 15 of 24	1	NM_020366.4	ENSP00000382895.2		Q96KN7-1

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29940

AN:

152070

Hom.:

3235

Cov.:

show subpopulations

Gnomad AFR

AF:

0.173

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.176

Gnomad EAS

AF:

0.00539

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.181

GnomAD2 exomes

AF:

0.191

AC:

46320

AN:

242254

AF XY:

0.197

show subpopulations

Gnomad AFR exome

AF:

0.170

Gnomad AMR exome

AF:

0.0948

Gnomad ASJ exome

AF:

0.190

Gnomad EAS exome

AF:

0.00431

Gnomad FIN exome

AF:

0.257

Gnomad NFE exome

AF:

0.233

Gnomad OTH exome

AF:

0.198

GnomAD4 exome

AF:

0.217

AC:

313602

AN:

1446874

Hom.:

35736

Cov.:

AF XY:

0.217

AC XY:

155901

AN XY:

717886

show subpopulations

African (AFR)

AF:

0.168

AC:

5536

AN:

33036

American (AMR)

AF:

0.101

AC:

4388

AN:

43382

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

4604

AN:

25438

East Asian (EAS)

AF:

0.00332

AC:

131

AN:

39420

South Asian (SAS)

AF:

0.212

AC:

18073

AN:

85218

European-Finnish (FIN)

AF:

0.261

AC:

13811

AN:

53004

Middle Eastern (MID)

AF:

0.202

AC:

1150

AN:

5704

European-Non Finnish (NFE)

AF:

0.230

AC:

253448

AN:

1102066

Other (OTH)

AF:

0.209

AC:

12461

AN:

59606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

12873

25746

38620

51493

64366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8500

17000

25500

34000

42500

<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:

0.197

AC:

29959

AN:

152188

Hom.:

3235

Cov.:

AF XY:

0.194

AC XY:

14450

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.173

AC:

7182

AN:

41518

American (AMR)

AF:

0.131

AC:

2006

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

611

AN:

3466

East Asian (EAS)

AF:

0.00540

AC:

AN:

5184

South Asian (SAS)

AF:

0.200

AC:

967

AN:

4826

European-Finnish (FIN)

AF:

0.243

AC:

2572

AN:

10586

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.233

AC:

15862

AN:

67994

Other (OTH)

AF:

0.180

AC:

381

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1234

2468

3701

4935

6169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.214

Hom.:

7408

Bravo

AF:

0.185

Asia WGS

AF:

0.108

AC:

377

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: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

- -

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:2

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

- -

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

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.3

(source)

DANN

Benign

0.47

PhyloP100

0.88

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0020

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