Variant chr16-53605610-G-A details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18990323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5 link	c.3706C>T	p.Arg1236Cys	missense_variant	Exon 26 of 27	ENST00000647211.2	NP_056087.2	Q68CZ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2 link	c.3706C>T	p.Arg1236Cys	missense_variant	Exon 26 of 27		NM_015272.5	ENSP00000493946.1		Q68CZ1-1

Frequencies

GnomAD3 genomes

AF:

0.000592

AC:

90

AN:

152152

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000546

AC:

137

AN:

251036

Hom.:

0

AF XY:

0.000649

AC XY:

88

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000925

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00104

AC:

1521

AN:

1461718

Hom.:

0

Cov.:

32

AF XY:

0.00102

AC XY:

745

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.000469

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.00108

GnomAD4 genome

AF:

0.000591

AC:

90

AN:

152270

Hom.:

0

Cov.:

32

AF XY:

0.000591

AC XY:

44

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000985

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000658

Hom.:

0

Bravo

AF:

0.000695

TwinsUK

AF:

0.00108

AC:

4

ALSPAC

AF:

0.00208

AC:

8

ESP6500AA

AF:

0.000910

AC:

4

ESP6500EA

AF:

0.00140

AC:

12

ExAC

AF:

0.000610

AC:

74

Asia WGS

AF:

0.000289

AC:

1

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect; R1236C failed to rescue morpholino phenotype in zebrafish and another study demonstrated impaired binding to EML1 (Khanna et al., 2009; Uzquiano et al., 2019); Observed with a missense variant on the opposite allele (in trans) in a patient with subcortical heterotopia (Uzquiano et al., 2019); Observed in an individual with a clinical diagnosis of Meckel-Gruber syndrome without a second variant in the RPGRIP1L gene identified (Khanna et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19430481, 31390572, 34426522, 36068917, 36061204) -

Nov 19, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jul 15, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RPGRIP1L c.3706C>T (p.Arg1236Cys) results in a non-conservative amino acid change located in the RPGRIP1, C-terminal domain (IPR041091) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 251036 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders (0.00055 vs 0.00079), allowing no conclusion about variant significance. c.3706C>T has been reported in the literature in an individual with a clinical diagnosis of Meckel syndrome but was heterozygous for this variant (Khanna_2009). Functional assessment for this variant in the zebrafish model was pathogenic (Khanna_2009). In a seperate study the variant impaired subcellular localization and interactions with EML1 (Uzquiano _2019). These reports do not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

RPGRIP1L-related disorder

Uncertain:1

Aug 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RPGRIP1L c.3706C>T variant is predicted to result in the amino acid substitution p.Arg1236Cys. This variant has been reported in an individual with Meckel syndrome in the absence of a second variant (Khanna et al. 2009. PubMed ID: 19430481) as well as in a fetus with Meckel syndrome in the compound heterozygous state to a likely pathogenic variant (Moreno-Leon et al. 2022. PubMed ID: 36061204). This variant has also been reported in the compound heterozygous state in an individual with subcortical heterotopia (Uzquiano et al. 2019. PubMed ID: 31390572). This variant is reported in 0.095% of alleles in individuals of European (non-Finnish) descent in gnomAD. While we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1236 of the RPGRIP1L protein (p.Arg1236Cys). This variant is present in population databases (rs151332923, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of RPGRIP1L-related conditions and/or Meckel syndrome (PMID: 19430481, 31390572). ClinVar contains an entry for this variant (Variation ID: 235636). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPGRIP1L protein function. Experimental studies have shown that this missense change affects RPGRIP1L function (PMID: 31390572). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Joubert syndrome 7

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Meckel syndrome, type 5

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

COACH syndrome 1

Uncertain:1

May 07, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Meckel syndrome, type 5;C1969053:Joubert syndrome 7;C5436841:COACH syndrome 3

Uncertain:1

Jan 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 8

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial aplasia of the vermis

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.032

T

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

22

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;.;T;.;.;.

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.84

D

LIST_S2

Benign

0.85

D;.;D;D;D;D

M_CAP

Benign

0.033

D

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Benign

-0.60

T

MutationAssessor

Uncertain

2.3

.;M;.;M;.;.

PrimateAI

Benign

0.36

T

PROVEAN

Pathogenic

-4.5

D;.;.;D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.016

D;.;.;D;D;D

Sift4G

Uncertain

0.032

D;.;D;D;D;D

Polyphen

0.27

B;B;.;B;.;.

Vest4

0.61

MVP

0.85

MPC

0.10

ClinPred

0.059

T

GERP RS

5.8

Varity_R

0.18

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

chr16-53605610-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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