chr16-53649037-C-T

Position:

chr16-53649037-C-T

Variant summary

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

The NM_015272.5(RPGRIP1L):c.2231G>A(p.Arg744Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,613,796 control chromosomes in the GnomAD database, including 1,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R744L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.032 ( 161 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1628 hom. )

Consequence

RPGRIP1L
NM_015272.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 2.43

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:

RPGRIP1L (HGNC:):

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=0.0016984642).

BP6

Variant 16-53649037-C-T is Benign according to our data. Variant chr16-53649037-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-53649037-C-T is described in Lovd as [Benign]. Variant chr16-53649037-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5 linkuse as main transcript	c.2231G>A	p.Arg744Gln	missense_variant	16/27	ENST00000647211.2	NP_056087.2	Q68CZ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2 linkuse as main transcript	c.2231G>A	p.Arg744Gln	missense_variant	16/27		NM_015272.5	ENSP00000493946.1		Q68CZ1-1

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

4793

AN:

152112

Hom.:

154

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0320

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.0946

Gnomad FIN

AF:

0.00688

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0350

Gnomad OTH

AF:

0.0344

GnomAD3 exomes

AF:

0.0462

AC:

11606

AN:

251400

Hom.:

513

AF XY:

0.0500

AC XY:

6798

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00861

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0380

Gnomad EAS exome

AF:

0.163

Gnomad SAS exome

AF:

0.0928

Gnomad FIN exome

AF:

0.00767

Gnomad NFE exome

AF:

0.0347

Gnomad OTH exome

AF:

0.0478

GnomAD4 exome

AF:

0.0386

AC:

56349

AN:

1461566

Hom.:

1628

Cov.:

AF XY:

0.0407

AC XY:

29559

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0108

Gnomad4 AMR exome

AF:

0.0245

Gnomad4 ASJ exome

AF:

0.0370

Gnomad4 EAS exome

AF:

0.133

Gnomad4 SAS exome

AF:

0.0921

Gnomad4 FIN exome

AF:

0.00799

Gnomad4 NFE exome

AF:

0.0331

Gnomad4 OTH exome

AF:

0.0452

GnomAD4 genome

AF:

0.0316

AC:

4804

AN:

152230

Hom.:

161

Cov.:

AF XY:

0.0324

AC XY:

2415

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0101

Gnomad4 AMR

AF:

0.0319

Gnomad4 ASJ

AF:

0.0337

Gnomad4 EAS

AF:

0.136

Gnomad4 SAS

AF:

0.0942

Gnomad4 FIN

AF:

0.00688

Gnomad4 NFE

AF:

0.0350

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0385

Hom.:

414

Bravo

AF:

0.0313

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0337

AC:

130

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0327

AC:

281

ExAC

AF:

0.0463

AC:

5619

Asia WGS

AF:

0.0990

AC:

343

AN:

3478

EpiCase

AF:

0.0419

EpiControl

AF:

0.0445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 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	Eurofins Ntd Llc (ga)	Sep 10, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Joubert syndrome 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

Meckel syndrome, type 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2019

- -

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. -

Familial aplasia of the vermis

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.028

.;.;T;.;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

D;.;D;D;D;D

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.3

M;M;.;M;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.99

N;.;.;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.040

D;.;.;T;T;T

Sift4G

Uncertain

0.034

D;.;D;D;D;D

Polyphen

1.0

D;D;.;D;.;.

Vest4

0.28

MPC

0.43

ClinPred

0.019

GERP RS

6.1

Varity_R

0.14

gMVP

0.59

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