Variant 14-21325943-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The ENST00000400017.7(RPGRIP1):c.2480G>T(p.Arg827Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,652 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R827H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RPGRIP1
ENST00000400017.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:2

Conservation

PhyloP100: 1.42

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-21325943-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 14-21325943-G-T is Pathogenic according to our data. Variant chr14-21325943-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4986.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-21325943-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.2480G>T	p.Arg827Leu	missense_variant	17/25	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.2480G>T	p.Arg827Leu	missense_variant	17/25	1	NM_020366.4	ENSP00000382895	P2	Q96KN7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cone-rod dystrophy 13

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2003	- -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

May 27, 2024

- -

not provided

Other:1

not provided, no classification provided

literature only

Retina International

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;D;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.8

.;M;.

MutationTaster

Benign

0.99

A;A;A;A;A;A;A

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.99, 0.99

.;D;D

Vest4

0.84

MutPred

0.82

.;Loss of catalytic residue at R827 (P = 0.0609);.;

MVP

0.92

MPC

0.38

ClinPred

0.99

GERP RS

2.9

Varity_R

0.33

gMVP

0.69

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