rs151212590

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_015272.5(RPGRIP1L):​c.251G>A​(p.Arg84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,976 control chromosomes in the GnomAD database, including 2 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

Genomes: 𝑓 0.00058 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

RPGRIP1L
NM_015272.5 missense

Scores

9
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 2.79
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 Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04299715).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000578 (88/152156) while in subpopulation AMR AF= 0.00295 (45/15270). AF 95% confidence interval is 0.00226. There are 1 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RPGRIP1LNM_015272.5 linkuse as main transcriptc.251G>A p.Arg84Gln missense_variant 4/27 ENST00000647211.2 NP_056087.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RPGRIP1LENST00000647211.2 linkuse as main transcriptc.251G>A p.Arg84Gln missense_variant 4/27 NM_015272.5 ENSP00000493946 Q68CZ1-1

Frequencies

GnomAD3 genomes
AF:
0.000579
AC:
88
AN:
152038
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00295
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000132
AC:
33
AN:
250374
Hom.:
0
AF XY:
0.000133
AC XY:
18
AN XY:
135744
show subpopulations
Gnomad AFR exome
AF:
0.000576
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000103
AC:
151
AN:
1461820
Hom.:
1
Cov.:
32
AF XY:
0.000107
AC XY:
78
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.000986
Gnomad4 AMR exome
AF:
0.000335
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000764
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000578
AC:
88
AN:
152156
Hom.:
1
Cov.:
32
AF XY:
0.000524
AC XY:
39
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.000723
Gnomad4 AMR
AF:
0.00295
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000145
Hom.:
0
Bravo
AF:
0.000774
ESP6500AA
AF:
0.000457
AC:
2
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000148
AC:
18
EpiCase
AF:
0.000382
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 05, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 18, 2021In 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 -
RPGRIP1L-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 21, 2024The RPGRIP1L c.251G>A variant is predicted to result in the amino acid substitution p.Arg84Gln. This variant has been reported in three individuals with obesity (Melendez-Montañez and De Jesus-Rojas. 2024. PubMed ID: 38674329). This variant is reported in 0.062% of alleles in individuals of African descent in gnomAD, which is likely too common to be a 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. -
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. -
Meckel syndrome, type 5 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 syndrome, type 5;C1969053:Joubert syndrome 7;C5435651:COACH syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
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. -
Familial aplasia of the vermis Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Aug 06, 2020- -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
.;.;T;.;.;.;.;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.93
D;.;D;D;D;D;D;D
M_CAP
Benign
0.048
D
MetaRNN
Benign
0.043
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Benign
1.7
L;L;.;L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.2
D;.;.;D;D;D;D;.
REVEL
Uncertain
0.42
Sift
Benign
0.066
T;.;.;T;T;T;T;.
Sift4G
Benign
0.097
T;.;T;T;T;T;D;.
Polyphen
0.99
D;D;.;D;.;.;.;.
Vest4
0.57
MVP
0.76
MPC
0.45
ClinPred
0.060
T
GERP RS
5.8
Varity_R
0.28
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs151212590; hg19: chr16-53726256; COSMIC: COSV50902552; COSMIC: COSV50902552; API