rs111775292

Positions:

Variant summary

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

The NM_015272.5(RPGRIP1L):c.3428C>G(p.Thr1143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 661,030 control chromosomes in the GnomAD database, including 6,724 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1143N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.14 ( 1579 hom., cov: 28)

Exomes 𝑓: 0.14 ( 5145 hom. )

Consequence

RPGRIP1L
NM_015272.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.252

Variant links:

Genes affected

RPGRIP1L (HGNC:29168): (RPGRIP1 like) The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). [provided by RefSeq, Jun 2016]

RPGRIP1L 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=0.001986444).

BP6

Variant 16-53622223-G-C is Benign according to our data. Variant chr16-53622223-G-C is described in ClinVar as [Benign]. Clinvar id is 95692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-53622223-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1L	NM_015272.5 linkuse as main transcript	c.3428C>G	p.Thr1143Ser	missense_variant	23/27	ENST00000647211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1L	ENST00000647211.2 linkuse as main transcript	c.3428C>G	p.Thr1143Ser	missense_variant	23/27		NM_015272.5		Q68CZ1-1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21487

AN:

151032

Hom.:

1577

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.147

Gnomad OTH

AF:

0.151

GnomAD3 exomes

AF:

0.122

AC:

12371

AN:

101682

Hom.:

880

AF XY:

0.124

AC XY:

6975

AN XY:

56274

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.0813

Gnomad ASJ exome

AF:

0.154

Gnomad EAS exome

AF:

0.108

Gnomad SAS exome

AF:

0.122

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.136

AC:

69476

AN:

509880

Hom.:

5145

Cov.:

AF XY:

0.137

AC XY:

37737

AN XY:

275208

show subpopulations

Gnomad4 AFR exome

AF:

0.150

Gnomad4 AMR exome

AF:

0.0827

Gnomad4 ASJ exome

AF:

0.156

Gnomad4 EAS exome

AF:

0.105

Gnomad4 SAS exome

AF:

0.127

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.146

Gnomad4 OTH exome

AF:

0.142

GnomAD4 genome

AF:

0.142

AC:

21487

AN:

151150

Hom.:

1579

Cov.:

AF XY:

0.140

AC XY:

10362

AN XY:

73784

show subpopulations

Gnomad4 AFR

AF:

0.156

Gnomad4 AMR

AF:

0.118

Gnomad4 ASJ

AF:

0.139

Gnomad4 EAS

AF:

0.124

Gnomad4 SAS

AF:

0.121

Gnomad4 FIN

AF:

0.115

Gnomad4 NFE

AF:

0.147

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.143

Hom.:

275

Bravo

AF:

0.140

TwinsUK

AF:

0.133

AC:

495

ALSPAC

AF:

0.135

AC:

522

ExAC

AF:

0.107

AC:

1474

Asia WGS

AF:

0.111

AC:

387

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joubert syndrome 7

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	Jul 10, 2021	- -

Meckel syndrome, type 5

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	Jul 10, 2021	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Nephronophthisis 8

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.42

DANN

Benign

0.11

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0038

LIST_S2

Benign

0.093

.;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.39

PROVEAN

Benign

0.26

.;N;N

REVEL

Benign

0.038

Sift

Benign

0.76

.;T;T

Sift4G

Benign

0.95

.;T;T

Polyphen

0.0050

B;B;.

Vest4

0.028, 0.0080

MutPred

0.28

Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);.;

MPC

0.065

ClinPred

0.0015

GERP RS

0.16

Varity_R

0.060

gMVP

0.12

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