rs10151259

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.1639G>T(p.Ala547Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,611,936 control chromosomes in the GnomAD database, including 43,592 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3773 hom., cov: 31)

Exomes 𝑓: 0.23 ( 39819 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:18O:2

Conservation

PhyloP100: 1.17

Publications

35 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=0.0019745529).

BP6

Variant 14-21321881-G-T is Benign according to our data. Variant chr14-21321881-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 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.1639G>T	p.Ala547Ser	missense	Exon 14 of 25	NP_065099.3
RPGRIP1	NM_001377948.1		c.565G>T	p.Ala189Ser	missense	Exon 4 of 15	NP_001364877.1
RPGRIP1	NM_001377949.1		c.565G>T	p.Ala189Ser	missense	Exon 4 of 13	NP_001364878.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.1639G>T	p.Ala547Ser	missense	Exon 14 of 25	ENSP00000382895.2
RPGRIP1	ENST00000555587.5	TSL:1	c.64G>T	p.Ala22Ser	missense	Exon 2 of 13	ENSP00000451262.1
RPGRIP1	ENST00000382933.8	TSL:1	c.565G>T	p.Ala189Ser	missense	Exon 4 of 12	ENSP00000372391.4

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32628

AN:

151950

Hom.:

3773

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.231

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.00692

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.243

Gnomad OTH

AF:

0.202

GnomAD2 exomes

AF:

0.201

AC:

49711

AN:

247634

AF XY:

0.206

show subpopulations

Gnomad AFR exome

AF:

0.209

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.205

Gnomad EAS exome

AF:

0.00536

Gnomad FIN exome

AF:

0.271

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.209

GnomAD4 exome

AF:

0.228

AC:

332788

AN:

1459868

Hom.:

39819

Cov.:

AF XY:

0.228

AC XY:

165737

AN XY:

726166

show subpopulations

African (AFR)

AF:

0.209

AC:

6997

AN:

33428

American (AMR)

AF:

0.110

AC:

4904

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.199

AC:

5194

AN:

26090

East Asian (EAS)

AF:

0.00398

AC:

158

AN:

39682

South Asian (SAS)

AF:

0.224

AC:

19262

AN:

86002

European-Finnish (FIN)

AF:

0.278

AC:

14840

AN:

53352

Middle Eastern (MID)

AF:

0.222

AC:

1277

AN:

5764

European-Non Finnish (NFE)

AF:

0.240

AC:

266722

AN:

1110694

Other (OTH)

AF:

0.223

AC:

13434

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

11696

23392

35088

46784

58480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8880

17760

26640

35520

44400

<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:

0.215

AC:

32661

AN:

152068

Hom.:

3773

Cov.:

AF XY:

0.212

AC XY:

15773

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.212

AC:

8804

AN:

41462

American (AMR)

AF:

0.142

AC:

2169

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

704

AN:

3466

East Asian (EAS)

AF:

0.00694

AC:

AN:

5188

South Asian (SAS)

AF:

0.213

AC:

1025

AN:

4820

European-Finnish (FIN)

AF:

0.254

AC:

2690

AN:

10570

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.243

AC:

16508

AN:

67978

Other (OTH)

AF:

0.206

AC:

435

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1268

2536

3805

5073

6341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<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:

0.226

Hom.:

10365

Bravo

AF:

0.203

TwinsUK

AF:

0.240

AC:

890

ALSPAC

AF:

0.245

AC:

945

ESP6500AA

AF:

0.205

AC:

775

ESP6500EA

AF:

0.245

AC:

2017

ExAC

AF:

0.206

AC:

24875

Asia WGS

AF:

0.136

AC:

475

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Cone-rod dystrophy 13 (4)

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (2)

not provided (3)

Leber congenital amaurosis 1 (1)

Leber congenital amaurosis 6 (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

0.0087

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

1.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.36

Sift

Benign

0.32

Sift4G

Benign

0.26

Polyphen

1.0

Vest4

0.096

MPC

0.12

ClinPred

0.027

GERP RS

3.0

Varity_R

0.050

gMVP

0.18

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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