chr14-21328625-G-C

Position:

chr14-21328625-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020366.4(RPGRIP1):c.3097G>C(p.Glu1033Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,602,658 control chromosomes in the GnomAD database, including 97,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 6860 hom., cov: 31)

Exomes 𝑓: 0.34 ( 90153 hom. )

Consequence

RPGRIP1
NM_020366.4 missense, splice_region

Scores

Splicing: ADA: 0.00005508

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.30

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=0.00586462).

BP6

Variant 14-21328625-G-C is Benign according to our data. Variant chr14-21328625-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21328625-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.3097G>C	p.Glu1033Gln	missense_variant, splice_region_variant	19/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7 linkuse as main transcript	c.3097G>C	p.Glu1033Gln	missense_variant, splice_region_variant	19/25	1	NM_020366.4	P2	Q96KN7-1

Frequencies

GnomAD3 genomes

AF:

0.266

AC:

40432

AN:

151866

Hom.:

6860

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0632

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.231

Gnomad ASJ

AF:

0.256

Gnomad EAS

AF:

0.398

Gnomad SAS

AF:

0.488

Gnomad FIN

AF:

0.377

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.355

Gnomad OTH

AF:

0.285

GnomAD3 exomes

AF:

0.331

AC:

82392

AN:

248546

Hom.:

15237

AF XY:

0.345

AC XY:

46534

AN XY:

134898

show subpopulations

Gnomad AFR exome

AF:

0.0595

Gnomad AMR exome

AF:

0.198

Gnomad ASJ exome

AF:

0.250

Gnomad EAS exome

AF:

0.413

Gnomad SAS exome

AF:

0.484

Gnomad FIN exome

AF:

0.390

Gnomad NFE exome

AF:

0.351

Gnomad OTH exome

AF:

0.340

GnomAD4 exome

AF:

0.345

AC:

500377

AN:

1450672

Hom.:

90153

Cov.:

AF XY:

0.350

AC XY:

252797

AN XY:

722254

show subpopulations

Gnomad4 AFR exome

AF:

0.0516

Gnomad4 AMR exome

AF:

0.203

Gnomad4 ASJ exome

AF:

0.253

Gnomad4 EAS exome

AF:

0.377

Gnomad4 SAS exome

AF:

0.477

Gnomad4 FIN exome

AF:

0.400

Gnomad4 NFE exome

AF:

0.348

Gnomad4 OTH exome

AF:

0.337

GnomAD4 genome

AF:

0.266

AC:

40431

AN:

151986

Hom.:

6860

Cov.:

AF XY:

0.272

AC XY:

20183

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0631

Gnomad4 AMR

AF:

0.231

Gnomad4 ASJ

AF:

0.256

Gnomad4 EAS

AF:

0.399

Gnomad4 SAS

AF:

0.487

Gnomad4 FIN

AF:

0.377

Gnomad4 NFE

AF:

0.355

Gnomad4 OTH

AF:

0.288

Alfa

AF:

0.337

Hom.:

7031

Bravo

AF:

0.240

TwinsUK

AF:

0.334

AC:

1239

ALSPAC

AF:

0.361

AC:

1393

ESP6500AA

AF:

0.0709

AC:

265

ESP6500EA

AF:

0.352

AC:

2888

ExAC

AF:

0.336

AC:

40626

Asia WGS

AF:

0.453

AC:

1573

AN:

3478

EpiCase

AF:

0.347

EpiControl

AF:

0.327

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cone-rod dystrophy 13

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	This variant is associated with the following publications: (PMID: 21857984, 16123401, 20079931) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Leber congenital amaurosis 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.048

DEOGEN2

Benign

0.0012

T;T;T;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.61

T;T;T;T;T

MetaRNN

Benign

0.0059

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.94

.;.;N;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

0.83

N;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.99

T;T;T;T;T

Sift4G

Benign

0.59

T;T;T;T;T

Polyphen

0.0, 0.0010

.;.;B;B;B

Vest4

0.039

MPC

0.065

ClinPred

0.00094

GERP RS

1.8

Varity_R

0.049

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.018

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