chr16-53652951-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_015272.5(RPGRIP1L):āc.1736A>Gā(p.Tyr579Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000465 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00021 ( 0 hom., cov: 32)
Exomes š: 0.000029 ( 0 hom. )
Consequence
RPGRIP1L
NM_015272.5 missense
NM_015272.5 missense
Scores
1
13
5
Clinical Significance
Conservation
PhyloP100: 3.60
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]
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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=0.13801613).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RPGRIP1L | NM_015272.5 | c.1736A>G | p.Tyr579Cys | missense_variant | 15/27 | ENST00000647211.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RPGRIP1L | ENST00000647211.2 | c.1736A>G | p.Tyr579Cys | missense_variant | 15/27 | NM_015272.5 |
Frequencies
GnomAD3 genomes 0.000210 AC: 32AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000997 AC: 25AN: 250862Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135596
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461516Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727048
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GnomAD4 genome 0.000210 AC: 32AN: 152344Hom.: 0 Cov.: 32 AF XY: 0.000174 AC XY: 13AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 29, 2015 | - - |
RPGRIP1L-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 08, 2024 | The RPGRIP1L c.1736A>G variant is predicted to result in the amino acid substitution p.Tyr579Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.076% of alleles in individuals of African descent in gnomAD, which may be too common to be an undocumented primary cause of disease. 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. - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 579 of the RPGRIP1L protein (p.Tyr579Cys). This variant is present in population databases (rs148230131, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with RPGRIP1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 235333). 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 not expected to disrupt RPGRIP1L protein function. 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
| 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 syndrome, type 5 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 syndrome, type 5;C1969053:Joubert syndrome 7;C5436841:COACH syndrome 3 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 22, 2022 | - - |
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. - |
Familial aplasia of the vermis Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 14, 2020 | - - |
Inborn genetic diseases Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.;M;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;D;D;D
Sift4G
Uncertain
D;.;D;D;D;D
Polyphen
D;P;.;P;.;.
Vest4
MVP
MPC
0.47
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at