14-21307738-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_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

Publications

0 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: Benign. The variant received -9 ACMG points.

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 VariationId is 221937.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 link	c.808A>G	p.Ile270Val	missense_variant	Exon 7 of 25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RPGRIP1	ENST00000400017.7 link	c.808A>G	p.Ile270Val	missense_variant	Exon 7 of 25	1	NM_020366.4	ENSP00000382895.2
RPGRIP1	ENST00000557771.5 link	c.727A>G	p.Ile243Val	missense_variant	Exon 6 of 24	5		ENSP00000451219.1
RPGRIP1	ENST00000556336.5 link	c.727A>G	p.Ile243Val	missense_variant	Exon 6 of 21	5		ENSP00000450445.1

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

GnomAD2 exomes

AF:

0.000143

AC:

AN:

174474

AF XY:

0.000119

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 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

African (AFR)

AF:

0.00218

AC:

AN:

32136

American (AMR)

AF:

0.000383

AC:

AN:

36538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25270

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37222

South Asian (SAS)

AF:

0.00

AC:

AN:

79424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1079818

Other (OTH)

AF:

0.000223

AC:

AN:

58398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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:

0.000761

AC:

116

AN:

152352

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00252

AC:

105

AN:

41586

American (AMR)

AF:

0.000523

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000247

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

Dec 12, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Apr 14, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 6

Uncertain:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RPGRIP1-related disorder

Benign:1

May 25, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Anophthalmia-microphthalmia syndrome

Benign:1

Jan 01, 2013

Paul Sabatier University EA-4555, Paul Sabatier University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

MutationAssessor

Uncertain

2.7

.;.;M

PhyloP100

4.3

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

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over