14-21348273-G-A

Position:

chr14-21348273-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_020366.4(RPGRIP1):c.3719G>A(p.Gly1240Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,586,636 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 137 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 125 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.88

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 -18 ACMG points.

PM1

In a region_of_interest Interaction with RPGR (size 190) in uniprot entity RPGR1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_020366.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0024254918).

BP6

Variant 14-21348273-G-A is Benign according to our data. Variant chr14-21348273-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 312800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4 link	c.3719G>A	p.Gly1240Glu	missense_variant	24/25	ENST00000400017.7	NP_065099.3	Q96KN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7 link	c.3719G>A	p.Gly1240Glu	missense_variant	24/25	1	NM_020366.4	ENSP00000382895.2		Q96KN7-1

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3439

AN:

152118

Hom.:

136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0782

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00819

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00616

AC:

1300

AN:

211026

Hom.:

AF XY:

0.00456

AC XY:

516

AN XY:

113126

show subpopulations

Gnomad AFR exome

AF:

0.0811

Gnomad AMR exome

AF:

0.00430

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000367

Gnomad OTH exome

AF:

0.00487

GnomAD4 exome

AF:

0.00250

AC:

3590

AN:

1434400

Hom.:

125

Cov.:

AF XY:

0.00217

AC XY:

1540

AN XY:

711102

show subpopulations

Gnomad4 AFR exome

AF:

0.0825

Gnomad4 AMR exome

AF:

0.00492

Gnomad4 ASJ exome

AF:

0.00223

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000112

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000250

Gnomad4 OTH exome

AF:

0.00547

GnomAD4 genome

AF:

0.0226

AC:

3442

AN:

152236

Hom.:

137

Cov.:

AF XY:

0.0216

AC XY:

1611

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0780

Gnomad4 AMR

AF:

0.00812

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00697

Hom.:

Bravo

AF:

0.0267

ESP6500AA

AF:

0.0678

AC:

253

ESP6500EA

AF:

0.000851

AC:

ExAC

AF:

0.00669

AC:

807

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 14, 2018

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cone-rod dystrophy 13

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Leber congenital amaurosis 6

Benign:1

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

T;T;T;.;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.81

T;T;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.3

.;.;M;.;.

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-4.8

D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Benign

0.035

D;T;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D

Polyphen

0.84, 0.97, 0.90

.;.;P;D;P

Vest4

0.29

MVP

0.85

MPC

0.38

ClinPred

0.049

GERP RS

4.5

Varity_R

0.51

gMVP

0.59

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