rs62646879

Positions:

chr14-21301003-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000400017.7(RPGRIP1):c.256C>T(p.Arg86Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,612,666 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 14 hom., cov: 30)

Exomes 𝑓: 0.00085 ( 19 hom. )

Consequence

RPGRIP1
ENST00000400017.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.283

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003682822).

BP6

Variant 14-21301003-C-T is Benign according to our data. Variant chr14-21301003-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 99816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21301003-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00836 (1273/152332) while in subpopulation AFR AF= 0.0291 (1209/41570). AF 95% confidence interval is 0.0277. There are 14 homozygotes in gnomad4. There are 582 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.256C>T	p.Arg86Trp	missense_variant	4/25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7 linkuse as main transcript	c.256C>T	p.Arg86Trp	missense_variant	4/25	1	NM_020366.4	ENSP00000382895	P2	Q96KN7-1
RPGRIP1	ENST00000557771.5 linkuse as main transcript	c.256C>T	p.Arg86Trp	missense_variant	3/24	5		ENSP00000451219	A2
RPGRIP1	ENST00000556336.5 linkuse as main transcript	c.256C>T	p.Arg86Trp	missense_variant	3/21	5		ENSP00000450445

Frequencies

GnomAD3 genomes

AF:

0.00836

AC:

1272

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

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:

0.000103

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00186

AC:

453

AN:

243620

Hom.:

AF XY:

0.00131

AC XY:

175

AN XY:

133348

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.000580

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:

0.0000552

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.000847

AC:

1237

AN:

1460334

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

522

AN XY:

726412

show subpopulations

Gnomad4 AFR exome

AF:

0.0317

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00161

GnomAD4 genome

AF:

0.00836

AC:

1273

AN:

152332

Hom.:

Cov.:

AF XY:

0.00781

AC XY:

582

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0291

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.000979

Hom.:

Bravo

AF:

0.00928

ESP6500AA

AF:

0.0245

AC:

ESP6500EA

AF:

0.000124

AC:

ExAC

AF:

0.00235

AC:

283

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Cone-rod dystrophy 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Leber congenital amaurosis 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.097

T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.83

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

.;.;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Benign

0.087

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

0.98

.;.;D

Vest4

0.30

MVP

0.62

MPC

0.25

ClinPred

0.044

GERP RS

0.48

Varity_R

0.14

gMVP

0.43

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