rs10151259

Positions:

chr14-21321881-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000400017.7(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. 13/20 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
ENST00000400017.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:17O:2

Conservation

PhyloP100: 1.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 4987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21321881-G-T is described in Lovd as [Benign]. Variant chr14-21321881-G-T is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.1639G>T	p.Ala547Ser	missense_variant	14/25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7 linkuse as main transcript	c.1639G>T	p.Ala547Ser	missense_variant	14/25	1	NM_020366.4	ENSP00000382895	P2	Q96KN7-1

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

GnomAD3 exomes

AF:

0.201

AC:

49711

AN:

247634

Hom.:

5831

AF XY:

0.206

AC XY:

27701

AN XY:

134368

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 SAS exome

AF:

0.226

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

Gnomad4 AFR exome

AF:

0.209

Gnomad4 AMR exome

AF:

0.110

Gnomad4 ASJ exome

AF:

0.199

Gnomad4 EAS exome

AF:

0.00398

Gnomad4 SAS exome

AF:

0.224

Gnomad4 FIN exome

AF:

0.278

Gnomad4 NFE exome

AF:

0.240

Gnomad4 OTH exome

AF:

0.223

GnomAD4 genome

AF:

0.215

AC:

32661

AN:

152068

Hom.:

3773

Cov.:

AF XY:

0.212

AC XY:

15773

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.203

Gnomad4 EAS

AF:

0.00694

Gnomad4 SAS

AF:

0.213

Gnomad4 FIN

AF:

0.254

Gnomad4 NFE

AF:

0.243

Gnomad4 OTH

AF:

0.206

Alfa

AF:

0.231

Hom.:

3523

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

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:17Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cone-rod dystrophy 13

Pathogenic:1Benign:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2003	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	Population allele frequency is 20% (rs10151259, 56,258/275,596 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Leber congenital amaurosis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Leber congenital amaurosis 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

Retinal dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;T;T;.;T;.

Eigen

Benign

0.0087

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.81

T;T;T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

.;.;M;.;.;.

MutationTaster

Benign

0.98

P;P;P;P;P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

N;N;N;N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.32

T;T;T;T;T;T

Sift4G

Benign

0.26

T;D;D;T;D;D

Polyphen

1.0, 0.97

.;.;D;D;D;.

Vest4

0.096

MPC

0.12

ClinPred

0.027

GERP RS

3.0

Varity_R

0.050

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over