rs10151259

Variant names:

• chr14-21321881-G-T
• rs10151259
• NM_020366.4:c.1639G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020366.4(RPGRIP1):​c.1639G>T​(p.Ala547Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,611,936 control chromosomes in the GnomAD database, including 43,592 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3773 hom., cov: 31)
  • Exomes 𝑓: 0.23 (39819 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:17 O:2
• Conservation: PhyloP100: 1.17

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019745529).
• BP6: Variant 14-21321881-G-T is Benign according to our data. Variant chr14-21321881-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 4987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21321881-G-T is described in Lovd as [Benign]. Variant chr14-21321881-G-T is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.1639G>T	p.Ala547Ser	missense_variant	Exon 14 of 25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.1639G>T	p.Ala547Ser	missense_variant	Exon 14 of 25	1	NM_020366.4	ENSP00000382895.2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32628 AN: 151950 Hom.: 3773 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.00692

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.201 AC: 49711 AN: 247634 Hom.: 5831 AF XY: 0.206 AC XY: 27701 AN XY: 134368

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.00536

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.228 AC: 332788 AN: 1459868 Hom.: 39819 Cov.: 32 AF XY: 0.228 AC XY: 165737 AN XY: 726166

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.00398

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.240

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.215 AC: 32661 AN: 152068 Hom.: 3773 Cov.: 31 AF XY: 0.212 AC XY: 15773 AN XY: 74336

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.00694

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.206

Alfa AF: 0.231 Hom.: 3523

Bravo AF: 0.203

TwinsUK AF: 0.240 AC: 890

ALSPAC AF: 0.245 AC: 945

ESP6500AA AF: 0.205 AC: 775

ESP6500EA AF: 0.245 AC: 2017

ExAC AF: 0.206 AC: 24875

Asia WGS AF: 0.136 AC: 475 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:17 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 13 Pathogenic:1 Benign:2 Other:1

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Population allele frequency is 20% (rs10151259, 56,258/275,596 alleles in gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2 Other:1

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 1 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 6 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Retinal dystrophy Benign:1

Jan 01, 2012

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T;T;T;.;T;.
Eigen	Benign	0.0087
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;.;M;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.32	T;T;T;T;T;T
Sift4G	Benign	0.26	T;D;D;T;D;D
Polyphen		1.0, 0.97	.;.;D;D;D;.
Vest4		0.096
MPC		0.12
ClinPred		0.027	T
GERP RS		3.0
Varity_R		0.050
gMVP		0.18

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

Other links and lift over

dbSNP: rs10151259; hg19: chr14-21790040; COSMIC: COSV52849538; COSMIC: COSV52849538;