rs143863631
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_015272.5(RPGRIP1L):c.1810G>A(p.Glu604Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000548 in 1,612,524 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_015272.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000407 AC: 62AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000404 AC: 101AN: 249866Hom.: 0 AF XY: 0.000356 AC XY: 48AN XY: 134982
GnomAD4 exome AF: 0.000562 AC: 821AN: 1460254Hom.: 7 Cov.: 32 AF XY: 0.000536 AC XY: 389AN XY: 726314
GnomAD4 genome 0.000407 AC: 62AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:2
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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: 29991045) -
RPGRIP1L-related disorder Uncertain:1
The RPGRIP1L c.1810G>A variant is predicted to result in the amino acid substitution p.Glu604Lys. This variant has been reported in the homozygous state in a patient with nephronophthisis-related ciliopathy, although pathogenicity was not determined (Kawaguchi et al. 2018. PubMed ID: 29991045). This variant is reported in 0.38% of alleles in individuals of Ashkenazi Jewish descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant has been reported in 0.01% of alleles in a subpopulation, including seven homozygous individuals. This variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/289611/). 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
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
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;C5435651:COACH syndrome 1 Uncertain:1
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Nephronophthisis 8 Uncertain:1
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
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Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
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Inborn genetic diseases Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at