chr16-53649028-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_015272.5(RPGRIP1L):​c.2240G>A​(p.Arg747Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,934 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

RPGRIP1L
NM_015272.5 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 1.38
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]

Genome browser will be placed here

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
RPGRIP1LNM_015272.5 linkuse as main transcriptc.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
RPGRIP1LENST00000647211.2 linkuse as main transcriptc.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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingBaylor GeneticsOct 01, 2020This 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 submitterclinical testingGeneDxMay 20, 2021This variant is associated with the following publications: (PMID: 22334370) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 15, 2015- -
RPGRIP1L-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 20, 2023The 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Familial aplasia of the vermis Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, 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.

Other links and lift over

dbSNP: rs142349647; hg19: chr16-53682940; COSMIC: COSV50907293; COSMIC: COSV50907293; API