14-21294745-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_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 Likely 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:9

Conservation

PhyloP100: 4.04

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

cone-rod dystrophy 13
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Leber congenital amaurosis 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RPGRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

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

PP5

Variant 14-21294745-C-T is Pathogenic according to our data. Variant chr14-21294745-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	NM_020366.4	MANE Select	c.154C>T	p.Arg52*	stop_gained	Exon 3 of 25	NP_065099.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.154C>T	p.Arg52*	stop_gained	Exon 3 of 25	ENSP00000382895.2
RPGRIP1	ENST00000557771.5	TSL:5	c.154C>T	p.Arg52*	stop_gained	Exon 2 of 24	ENSP00000451219.1
RPGRIP1	ENST00000556336.5	TSL:5	c.154C>T	p.Arg52*	stop_gained	Exon 2 of 21	ENSP00000450445.1

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

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

249074

AF XY:

0.00000740

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 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

African (AFR)

AF:

0.0000598

AC:

AN:

33424

American (AMR)

AF:

0.0000224

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39536

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110402

Other (OTH)

AF:

0.0000166

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000398

AC:

AN:

150874

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73564

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

41046

American (AMR)

AF:

0.00

AC:

AN:

15082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67908

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000301

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cone-rod dystrophy 13

Pathogenic:3

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:reference population

Nov 07, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 30, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

Pathogenic:2

May 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is present in population databases (rs192003551, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with inherited retinal disorders (PMID: 23105016, 28456785, 31736247). ClinVar contains an entry for this variant (Variation ID: 195355). For these reasons, this variant has been classified as Pathogenic.

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leber congenital amaurosis 6

Pathogenic:2

Nov 07, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

not provided

Pathogenic:1

Mar 02, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa

Pathogenic:1

Oct 01, 2024

Lab De Baere, Eye and Developmental Genetics Lab, Ghent University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG/AMP guidelines: PVS1, PM2, PP5

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.87

PhyloP100

4.0

Vest4

0.79

GERP RS

4.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over