rs34067949

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020366.4(RPGRIP1):c.1767G>T(p.Gln589His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,612,740 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 20 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.99

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=0.010454863).

BP6

Variant 14-21324622-G-T is Benign according to our data. Variant chr14-21324622-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 381682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21324622-G-T is described in Lovd as [Likely_benign]. Variant chr14-21324622-G-T is described in Lovd as [Pathogenic]. Variant chr14-21324622-G-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00343 (522/152256) while in subpopulation AMR AF= 0.00635 (97/15286). AF 95% confidence interval is 0.00532. There are 3 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.1767G>T	p.Gln589His	missense_variant	15/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7 linkuse as main transcript	c.1767G>T	p.Gln589His	missense_variant	15/25	1	NM_020366.4	P2	Q96KN7-1

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

522

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00511

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00287

AC:

713

AN:

248084

Hom.:

AF XY:

0.00296

AC XY:

399

AN XY:

134796

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00499

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00501

AC:

7313

AN:

1460484

Hom.:

Cov.:

AF XY:

0.00486

AC XY:

3531

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00210

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000591

Gnomad4 FIN exome

AF:

0.00136

Gnomad4 NFE exome

AF:

0.00610

Gnomad4 OTH exome

AF:

0.00424

GnomAD4 genome

AF:

0.00343

AC:

522

AN:

152256

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00635

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00512

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00440

Hom.:

Bravo

AF:

0.00343

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.00532

AC:

ExAC

AF:

0.00304

AC:

368

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00556

EpiControl

AF:

0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2016	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 17, 2024

- -

Cone-rod dystrophy 13

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

RPGRIP1: BS2 -

Leber congenital amaurosis 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.33

T;D;T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.34

T;T;T;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Uncertain

0.21

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.014

D;D;D;T

Polyphen

0.99, 0.96

.;D;D;.

Vest4

0.78

MutPred

0.61

.;Loss of ubiquitination at K591 (P = 0.074);.;.;

MVP

0.93

MPC

0.32

ClinPred

0.024

GERP RS

4.6

Varity_R

0.48

gMVP

0.66

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

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