chr16-53658782-A-G

Position:

chr16-53658782-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015272.5(RPGRIP1L):c.1340T>C(p.Leu447Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,593,768 control chromosomes in the GnomAD database, including 20 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L447L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 20 hom. )

Consequence

RPGRIP1L
NM_015272.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 3.41

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066491365).

BP6

Variant 16-53658782-A-G is Benign according to our data. Variant chr16-53658782-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193900.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=4, Uncertain_significance=1}. Variant chr16-53658782-A-G is described in Lovd as [Benign]. Variant chr16-53658782-A-G is described in Lovd as [Likely_benign]. Variant chr16-53658782-A-G is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00317 (483/152292) while in subpopulation NFE AF= 0.00497 (338/68010). AF 95% confidence interval is 0.00453. There are 0 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5 linkuse as main transcript	c.1340T>C	p.Leu447Ser	missense_variant	11/27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2 linkuse as main transcript	c.1340T>C	p.Leu447Ser	missense_variant	11/27		NM_015272.5	ENSP00000493946		Q68CZ1-1

Frequencies

GnomAD3 genomes

AF:

0.00317

AC:

483

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00310

AC:

728

AN:

234860

Hom.:

AF XY:

0.00314

AC XY:

397

AN XY:

126600

show subpopulations

Gnomad AFR exome

AF:

0.000589

Gnomad AMR exome

AF:

0.00135

Gnomad ASJ exome

AF:

0.00206

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000138

Gnomad FIN exome

AF:

0.00797

Gnomad NFE exome

AF:

0.00450

Gnomad OTH exome

AF:

0.00274

GnomAD4 exome

AF:

0.00432

AC:

6225

AN:

1441476

Hom.:

Cov.:

AF XY:

0.00425

AC XY:

3049

AN XY:

716664

show subpopulations

Gnomad4 AFR exome

AF:

0.000482

Gnomad4 AMR exome

AF:

0.00135

Gnomad4 ASJ exome

AF:

0.00244

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000154

Gnomad4 FIN exome

AF:

0.00873

Gnomad4 NFE exome

AF:

0.00489

Gnomad4 OTH exome

AF:

0.00402

GnomAD4 genome

AF:

0.00317

AC:

483

AN:

152292

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

229

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00734

Gnomad4 NFE

AF:

0.00497

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00394

Hom.:

Bravo

AF:

0.00267

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00306

AC:

371

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency + variant associated with BBS -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2017	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. -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RPGRIP1L: BP4, BS2 -

Meckel syndrome, type 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Familial aplasia of the vermis

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

.;.;T;.;.;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.026

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.64

T;.;T;T;T;T

MetaRNN

Benign

0.0066

T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.26

N;N;.;N;.;.

MutationTaster

Benign

0.92

N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.0

N;.;.;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.17

T;.;.;T;T;T

Sift4G

Benign

0.12

T;.;T;D;D;T

Polyphen

0.12

B;B;.;B;.;.

Vest4

0.43

MVP

0.76

MPC

0.12

ClinPred

0.012

GERP RS

5.9

Varity_R

0.085

gMVP

0.25

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