rs145896974

chr14-21325300-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_020366.4(RPGRIP1):c.2284C>T(p.Leu762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,612,554 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L762L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (18 hom.)
• Consequence: RPGRIP1 NM_020366.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 2.84

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 14-21325300-C-T is Benign according to our data. Variant chr14-21325300-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285038.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=3, Uncertain_significance=2}. Variant chr14-21325300-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00248 (378/152304) while in subpopulation NFE AF= 0.00365 (248/68022). AF 95% confidence interval is 0.00327. There are 1 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.2284C>T	p.Leu762=	synonymous_variant	16/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.2284C>T	p.Leu762=	synonymous_variant	16/25	1	NM_020366.4	P2

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00365

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00329 AC: 809 AN: 245544 Hom.: 4 AF XY: 0.00356 AC XY: 475 AN XY: 133254

Gnomad AFR exome AF: 0.000329

Gnomad AMR exome AF: 0.000971

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00537

Gnomad FIN exome AF: 0.00154

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00289 AC: 4217 AN: 1460250 Hom.: 18 Cov.: 32 AF XY: 0.00307 AC XY: 2227 AN XY: 726294

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00536

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00356

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74464

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00365

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00396 Hom.: 1

Bravo AF: 0.00242

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	RPGRIP1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cone-rod dystrophy 13 Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Leber congenital amaurosis 6 Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 04, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

RPGRIP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	7.7
Dann	Benign	0.73

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: rs145896974; hg19: chr14-21793459;