rs372615343

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_020366.4(RPGRIP1):c.808A>G(p.Ile270Val) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,557,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I270F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 4.35

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 Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01618126).

BP6

Variant 14-21307738-A-G is Benign according to our data. Variant chr14-21307738-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221937.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr14-21307738-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000761 (116/152352) while in subpopulation AFR AF= 0.00252 (105/41586). AF 95% confidence interval is 0.00213. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.808A>G	p.Ile270Val	missense_variant	7/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7 linkuse as main transcript	c.808A>G	p.Ile270Val	missense_variant	7/25	1	NM_020366.4	P2	Q96KN7-1
RPGRIP1	ENST00000557771.5 linkuse as main transcript	c.727A>G	p.Ile243Val	missense_variant	6/24	5		A2
RPGRIP1	ENST00000556336.5 linkuse as main transcript	c.727A>G	p.Ile243Val	missense_variant	6/21	5

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000143

AC:

AN:

174474

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

92572

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.000314

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000211

GnomAD4 exome

AF:

0.0000712

AC:

100

AN:

1404816

Hom.:

Cov.:

AF XY:

0.0000533

AC XY:

AN XY:

694344

show subpopulations

Gnomad4 AFR exome

AF:

0.00218

Gnomad4 AMR exome

AF:

0.000383

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000269

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.000223

GnomAD4 genome

AF:

0.000761

AC:

116

AN:

152352

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00252

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000247

Hom.:

Bravo

AF:

0.000786

ESP6500AA

AF:

0.00163

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000119

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 12, 2018

The RPGRIP1 c.808A>G; p.Ile270Val variant (rs372615343) is reported in the medical literature in an individual with an ocular development anomaly, but was not determined to be causative (Chassaing 2016). The variant is reported in the ClinVar database (Variation ID: 221937) and in the general population in 50 out of 205878 alleles. The amino acid at this position is moderately conserved across species but computational analyses (SIFT: Tolerated, PolyPhen-2: Probably Damaging) predict conflicting effects of this variant on protein structure/function. Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Chassaing N et al. Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network. Genome Res. 2016 Apr;26(4):474-85. -

Cone-rod dystrophy 13

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 14, 2016

- -

Leber congenital amaurosis 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

RPGRIP1-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Paul Sabatier University EA-4555, Paul Sabatier University

Jan 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

Cadd

Benign

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.071

T;T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-0.84

MutationTaster

Benign

0.82

D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.79

N;N;N

REVEL

Benign

0.069

Sift

Pathogenic

0.0

D;T;T

Sift4G

Benign

0.59

T;T;D

Polyphen

0.99

.;.;D

Vest4

0.37

MVP

0.56

MPC

0.37

ClinPred

0.094

GERP RS

4.9

Varity_R

0.23

gMVP

0.087

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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