rs34725281

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.3719G>A(p.Gly1240Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,586,636 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 137 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 125 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.88

Publications

7 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, STRONG Submitted by: PanelApp Australia, 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=0.0024254918).

BP6

Variant 14-21348273-G-A is Benign according to our data. Variant chr14-21348273-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGRIP1	NM_020366.4	MANE Select	c.3719G>A	p.Gly1240Glu	missense	Exon 24 of 25	NP_065099.3
RPGRIP1	NM_001377948.1		c.2645G>A	p.Gly882Glu	missense	Exon 14 of 15	NP_001364877.1
RPGRIP1	NM_001377949.1		c.1805G>A	p.Gly602Glu	missense	Exon 12 of 13	NP_001364878.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.3719G>A	p.Gly1240Glu	missense	Exon 24 of 25	ENSP00000382895.2	Q96KN7-1
RPGRIP1	ENST00000555587.5	TSL:1	c.2144G>A	p.Gly715Glu	missense	Exon 12 of 13	ENSP00000451262.1	G3V3I7
RPGRIP1	ENST00000382933.8	TSL:1	c.1697G>A	p.Gly566Glu	missense	Exon 11 of 12	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3439

AN:

152118

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0782

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00819

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.00616

AC:

1300

AN:

211026

AF XY:

0.00456

show subpopulations

Gnomad AFR exome

AF:

0.0811

Gnomad AMR exome

AF:

0.00430

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000367

Gnomad OTH exome

AF:

0.00487

GnomAD4 exome

AF:

0.00250

AC:

3590

AN:

1434400

Hom.:

125

Cov.:

AF XY:

0.00217

AC XY:

1540

AN XY:

711102

show subpopulations

African (AFR)

AF:

0.0825

AC:

2699

AN:

32734

American (AMR)

AF:

0.00492

AC:

195

AN:

39660

Ashkenazi Jewish (ASJ)

AF:

0.00223

AC:

AN:

25522

East Asian (EAS)

AF:

0.00

AC:

AN:

39100

South Asian (SAS)

AF:

0.000112

AC:

AN:

80346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52406

Middle Eastern (MID)

AF:

0.00524

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.000250

AC:

275

AN:

1099442

Other (OTH)

AF:

0.00547

AC:

325

AN:

59462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

138

275

413

550

688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0226

AC:

3442

AN:

152236

Hom.:

137

Cov.:

AF XY:

0.0216

AC XY:

1611

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0780

AC:

3238

AN:

41512

American (AMR)

AF:

0.00812

AC:

124

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68034

Other (OTH)

AF:

0.0180

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

148

296

444

592

740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00949

Hom.:

161

Bravo

AF:

0.0267

ESP6500AA

AF:

0.0678

AC:

253

ESP6500EA

AF:

0.000851

AC:

ExAC

AF:

0.00669

AC:

807

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Cone-rod dystrophy 13 (1)

Leber congenital amaurosis 6 (1)

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.3

PhyloP100

2.9

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.33

Sift

Benign

0.035

Sift4G

Uncertain

0.010

Polyphen

0.84

Vest4

0.29

MVP

0.85

MPC

0.38

ClinPred

0.049

GERP RS

4.5

Varity_R

0.51

gMVP

0.59

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over