Variant 16-53649028-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019827366).

BP6

Variant 16-53649028-C-T is Benign according to our data. Variant chr16-53649028-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166909.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}. Variant chr16-53649028-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5 linkuse as main transcript	c.2240G>A	p.Arg747Gln	missense_variant	16/27	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.2240G>A	p.Arg747Gln	missense_variant	16/27		NM_015272.5	ENSP00000493946		Q68CZ1-1

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152154

Hom.:

1

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000740

AC:

186

AN:

251422

Hom.:

0

AF XY:

0.000648

AC XY:

88

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00126

AC:

1846

AN:

1461662

Hom.:

5

Cov.:

31

AF XY:

0.00120

AC XY:

876

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00158

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152272

Hom.:

1

Cov.:

32

AF XY:

0.000645

AC XY:

48

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00151

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00121

Hom.:

1

Bravo

AF:

0.000778

TwinsUK

AF:

0.00108

AC:

4

ALSPAC

AF:

0.00104

AC:

4

ESP6500AA

AF:

0.000455

AC:

2

ESP6500EA

AF:

0.00174

AC:

15

ExAC

AF:

0.000749

AC:

91

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Meckel syndrome, type 5

Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 01, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	This variant is associated with the following publications: (PMID: 22334370) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -

RPGRIP1L-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

The RPGRIP1L c.2240G>A variant is predicted to result in the amino acid substitution p.Arg747Gln. This variant has been reported along with a second RPGRIP1L variant in an individual with retinitis pigmentosa (Table S5, Neveling et al. 2012. PubMed ID: 22334370), however the segregation and pathogenicity were not determined. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including a single homozygous individual, which may be too common to be a pathogenic variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Joubert syndrome 7

Uncertain: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. -

Nephronophthisis 8

Uncertain: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. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Familial aplasia of the vermis

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.44

T

BayesDel_noAF

Benign

-0.45

CADD

Benign

20

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

.;.;T;.;.;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.55

D

LIST_S2

Uncertain

0.87

D;.;D;D;D;D

M_CAP

Benign

0.018

T

MetaRNN

Benign

0.020

T;T;T;T;T;T

MetaSVM

Benign

-0.89

T

MutationAssessor

Benign

1.1

L;L;.;L;.;.

MutationTaster

Benign

0.66

N;N;N;N

PrimateAI

Benign

0.26

T

PROVEAN

Benign

-0.97

N;.;.;N;N;N

REVEL

Benign

0.063

Sift

Benign

0.21

T;.;.;T;T;T

Sift4G

Benign

0.19

T;.;T;T;T;T

Polyphen

0.010

B;B;.;B;.;.

Vest4

0.12

MVP

0.47

MPC

0.093

ClinPred

0.015

T

GERP RS

3.1

Varity_R

0.084

gMVP

0.41

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.

16-53649028-C-T

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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