rs6571751

Positions:

• chr14-21302571-A-G

Variant summary

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

The ENST00000400017.7(RPGRIP1):​c.574A>G​(p.Lys192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,561,794 control chromosomes in the GnomAD database, including 196,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18322 hom., cov: 32)
  • Exomes 𝑓: 0.50 (178335 hom.)
• Consequence: RPGRIP1 ENST00000400017.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.43

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=2.9413291E-5).
• BP6: Variant 14-21302571-A-G is Benign according to our data. Variant chr14-21302571-A-G is described in ClinVar as [Benign]. Clinvar id is 99827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21302571-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.574A>G	p.Lys192Glu	missense_variant	5/25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.574A>G	p.Lys192Glu	missense_variant	5/25	1	NM_020366.4	ENSP00000382895	P2
RPGRIP1	ENST00000557771.5	c.574A>G	p.Lys192Glu	missense_variant	4/24	5		ENSP00000451219	A2
RPGRIP1	ENST00000556336.5	c.574A>G	p.Lys192Glu	missense_variant	4/21	5		ENSP00000450445
RPGRIP1	ENST00000554750.1	n.173A>G		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74340 AN: 151930 Hom.: 18303 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.470

GnomAD3 exomes AF: 0.503 AC: 100555 AN: 199846 Hom.: 25617 AF XY: 0.508 AC XY: 54267 AN XY: 106836

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.327

Gnomad SAS exome AF: 0.607

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.502

GnomAD4 exome AF: 0.500 AC: 705005 AN: 1409746 Hom.: 178335 Cov.: 26 AF XY: 0.502 AC XY: 350608 AN XY: 697818

Gnomad4 AFR exome AF: 0.454

Gnomad4 AMR exome AF: 0.510

Gnomad4 ASJ exome AF: 0.416

Gnomad4 EAS exome AF: 0.307

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.544

Gnomad4 NFE exome AF: 0.502

Gnomad4 OTH exome AF: 0.487

GnomAD4 genome AF: 0.489 AC: 74409 AN: 152048 Hom.: 18322 Cov.: 32 AF XY: 0.492 AC XY: 36536 AN XY: 74312

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.494

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.322

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.471

Alfa AF: 0.499 Hom.: 50081

Bravo AF: 0.478

TwinsUK AF: 0.502 AC: 1863

ALSPAC AF: 0.499 AC: 1923

ESP6500AA AF: 0.448 AC: 1697

ESP6500EA AF: 0.498 AC: 4112

ExAC AF: 0.467 AC: 55358

Asia WGS AF: 0.507 AC: 1763 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cone-rod dystrophy 13 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

Leber congenital amaurosis 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

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	0.056
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.9
DANN	Benign	0.56
DEOGEN2	Benign	0.0019	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.24	T;T;T
MetaRNN	Benign	0.000029	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.28	.;.;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.4	N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.12
MPC		0.091
ClinPred		0.0022	T
GERP RS		3.1
Varity_R		0.058
gMVP		0.13

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

Other links and lift over

dbSNP: rs6571751; hg19: chr14-21770730; COSMIC: COSV52846904;