chr14-21294745-C-T

Position:

chr14-21294745-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020366.4(RPGRIP1):c.154C>T(p.Arg52*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000931 in 1,610,394 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RPGRIP1
NM_020366.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.04

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 18 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 14-21294745-C-T is Pathogenic according to our data. Variant chr14-21294745-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 195355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21294745-C-T is described in Lovd as [Pathogenic]. Variant chr14-21294745-C-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.154C>T	p.Arg52*	stop_gained	3/25	ENST00000400017.7	NP_065099.3	Q96KN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RPGRIP1	ENST00000400017.7 linkuse as main transcript	c.154C>T	p.Arg52*	stop_gained	3/25	1	NM_020366.4	ENSP00000382895.2	Q96KN7-1
RPGRIP1	ENST00000557771.5 linkuse as main transcript	c.154C>T	p.Arg52*	stop_gained	2/24	5		ENSP00000451219.1	G3V3F7
RPGRIP1	ENST00000556336.5 linkuse as main transcript	c.154C>T	p.Arg52*	stop_gained	2/21	5		ENSP00000450445.1	G3V236

Frequencies

GnomAD3 genomes

AF:

0.0000398

AC:

AN:

150782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249074

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459520

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726032

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000398

AC:

AN:

150874

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73564

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cone-rod dystrophy 13

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 30, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 195355). This premature translational stop signal has been observed in individual(s) with inherited retinal disorders (PMID: 23105016, 28456785, 31736247). This variant is present in population databases (rs192003551, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg52*) 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 15, 2024	- -

Leber congenital amaurosis 6

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 02, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.87

Vest4

0.79

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