rs75459701

Positions:

chr14-21325318-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_020366.4(RPGRIP1):c.2302C>T(p.Arg768Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000485 in 1,608,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

RPGRIP1
NM_020366.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 1.43

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 Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-21325318-C-T is Pathogenic according to our data. Variant chr14-21325318-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 566311.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=5}. Variant chr14-21325318-C-T is described in Lovd as [Pathogenic]. Variant chr14-21325318-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-21325318-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.2302C>T	p.Arg768Ter	stop_gained	16/25	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.2302C>T	p.Arg768Ter	stop_gained	16/25	1	NM_020366.4	ENSP00000382895	P2	Q96KN7-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000253

AC:

AN:

236808

Hom.:

AF XY:

0.0000311

AC XY:

AN XY:

128540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.0000588

Gnomad SAS exome

AF:

0.0000341

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000281

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000501

AC:

AN:

1456506

Hom.:

Cov.:

AF XY:

0.0000456

AC XY:

AN XY:

724046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000230

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000586

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000633

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change creates a premature translational stop signal (p.Arg768*) in the RPGRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGRIP1 are known to be pathogenic (PMID: 11528500, 23105016). This variant is present in population databases (rs75459701, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Leber congenital amaurosis or retinitis pigmentosa (PMID: 20079931). ClinVar contains an entry for this variant (Variation ID: 566311). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Cone-rod dystrophy 13

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2020

Reported with a second variant in multiple individuals diagnosed with retinitis pigmentosa or Leber congenital amaurosis in the published literature (Walia et al, 2010; Ge et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20079931, 26667666, 30072743, 32165824, 31589614) -

Leber congenital amaurosis 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

RPGRIP1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2023

The RPGRIP1 c.2302C>T variant is predicted to result in premature protein termination (p.Arg768*). This variant has previously been reported to be causative for Leber congenital amaurosis (Walia et al 2010. PubMed ID: 20079931; Ge Z et al 2015. PubMed ID: 26667666; Jamshidi F et al 2018. PubMed ID: 30072743; Zhu L et al 2021. PubMed ID: 33970760). This variant is reported in 0.010% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-21793477-C-T). Nonsense variants in RPGRIP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

RPGRIP1L-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 16, 2018

The RPGRIP1 c.2302C>T (p.Arg768Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg768Ter variant has been reported in two individuals from two different studies. A study of patients with Leber congenital amaurosis or early-onset retinitis pigmentosa identified one individual, whose exact phenotype was not described, who carried the p.Arg768Ter variant in a compound heterozygous state with a splice variant (Walia et al. 2010). Another individual with retinitis pigmentosa was found to carry the p.Arg768Ter variant along with two other missense variants, though the phase of these variants is not stated (Ge et al. 2015). Control data are unavailable for this variant, which is found at a frequency of 0.000039 in the Total population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of stop-gained variants, the p.Arg768Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for RPGRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.57

MutationTaster

Benign

1.0

A;A;A;A;A;N;N

Vest4

0.78

GERP RS

4.5

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