chr16-53619079-C-T
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_015272.5(RPGRIP1L):c.3562G>A(p.Val1188Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000639 in 1,614,038 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00049 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00066 ( 2 hom. )
Consequence
RPGRIP1L
NM_015272.5 missense
NM_015272.5 missense
Scores
19
Clinical Significance
Conservation
PhyloP100: 0.208
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 Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.022584975).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RPGRIP1L | NM_015272.5 | c.3562G>A | p.Val1188Met | missense_variant | 24/27 | ENST00000647211.2 | NP_056087.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RPGRIP1L | ENST00000647211.2 | c.3562G>A | p.Val1188Met | missense_variant | 24/27 | NM_015272.5 | ENSP00000493946 |
Frequencies
GnomAD3 genomes 0.000480 AC: 73AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000437 AC: 110AN: 251480Hom.: 0 AF XY: 0.000427 AC XY: 58AN XY: 135912
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GnomAD4 exome AF: 0.000655 AC: 958AN: 1461806Hom.: 2 Cov.: 31 AF XY: 0.000652 AC XY: 474AN XY: 727204
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GnomAD4 genome 0.000486 AC: 74AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43AN XY: 74430
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
RPGRIP1L-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2024 | The RPGRIP1L c.3562G>A variant is predicted to result in the amino acid substitution p.Val1188Met. This variant was reported in the compound heterozygous state in a patient with subcortical heterotopia; however, pathogenicity was not established (Uzquiano et al. 2019. PubMed ID: 31390572). This variant is reported in 0.21% of alleles in individuals of European (Finnish) descent in gnomAD, which is significantly more common than other known pathogenic variants in RPGRIP1L. Although we suspect this variant may be benign, at this time its clinical significance 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 12, 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 12, 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 12, 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. | Apr 24, 2020 | - - |
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 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;.;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;.;T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L;.;L;.;.
MutationTaster
Benign
N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;N;N
REVEL
Benign
Sift
Benign
T;.;.;T;T;T
Sift4G
Benign
T;.;T;T;T;T
Polyphen
P;P;.;P;.;.
Vest4
MVP
MPC
0.080
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