NM_020366.4:c.2480G>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_020366.4(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
NM_020366.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.42

Publications

11 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, STRONG Submitted by: PanelApp Australia, 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 VariationId is 4986.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGRIP1	NM_020366.4	MANE Select	c.2480G>T	p.Arg827Leu	missense	Exon 17 of 25	NP_065099.3
RPGRIP1	NM_001377948.1		c.1406G>T	p.Arg469Leu	missense	Exon 7 of 15	NP_001364877.1
RPGRIP1	NM_001377949.1		c.796+1218G>T		intron	N/A	NP_001364878.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.2480G>T	p.Arg827Leu	missense	Exon 17 of 25	ENSP00000382895.2	Q96KN7-1
RPGRIP1	ENST00000555587.5	TSL:1	c.905G>T	p.Arg302Leu	missense	Exon 5 of 13	ENSP00000451262.1	G3V3I7
RPGRIP1	ENST00000382933.8	TSL:1	c.689-1680G>T		intron	N/A	ENSP00000372391.4	Q96KN7-4

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111826

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

Cov.:

Alfa

AF:

0.0000133

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cone-rod dystrophy 13 (2)

Retinal dystrophy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.8

PhyloP100

1.4

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.014

Polyphen

0.99

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

Mutation Taster

=28/72

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over