rs137982921
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_015272.5(RPGRIP1L):āc.1156A>Gā(p.Lys386Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,613,608 control chromosomes in the GnomAD database, including 3 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
Publications
- Meckel syndrome, type 5Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
- Joubert syndrome 7Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- COACH syndrome 1Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Joubert syndrome with renal defectInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Meckel syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000979 AC: 149AN: 152216Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000846 AC: 212AN: 250614 AF XY: 0.000908 show subpopulations
GnomAD4 exome AF: 0.00120 AC: 1748AN: 1461274Hom.: 3 Cov.: 32 AF XY: 0.00120 AC XY: 871AN XY: 726964 show subpopulations
GnomAD4 genome 0.000978 AC: 149AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.000913 AC XY: 68AN XY: 74488 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:6
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The RPGRIP1L p.Lys386Glu variant was identified in 1 of 384 proband chromosomes (Frequency: 0.0026) from individuals with nephronophthisis-associated ciliopathy (Halbritter_2012_PMID:23188109). The variant was identified in dbSNP (ID: rs137982921) and ClinVar (classified as uncertain significance by Invitae, EGL Genetic Diagnostics, Fulgent Genetics, GeneDx, and Illumina). The variant was identified in control databases in 228 of 282020 chromosomes at a frequency of 0.0008085 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 54 of 35376 chromosomes (freq: 0.001526), Other in 10 of 7194 chromosomes (freq: 0.00139), European (non-Finnish) in 158 of 128734 chromosomes (freq: 0.001227), Ashkenazi Jewish in 2 of 10354 chromosomes (freq: 0.000193), European (Finnish) in 2 of 24848 chromosomes (freq: 0.00008) and African in 2 of 24964 chromosomes (freq: 0.00008), but was not observed in the East Asian or South Asian populations. The p.Lys386 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
The K386E variant in the RPGRIP1L gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the K386E variant is observed in 82/66610 (0.23%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The K386E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Lysine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K386E as a variant of uncertain significance. -
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BS1 -
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. -
Optic atrophy Uncertain:1
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Joubert syndrome Uncertain:1
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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. -
RPGRIP1L-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
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. -
Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at