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GeneBe

rs139974543

chr16-53619093-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015272.5(RPGRIP1L):c.3548C>G(p.Ala1183Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,613,978 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 3 hom., cov: 32)
Exomes 𝑓: 0.012 ( 120 hom. )

Consequence

RPGRIP1L
NM_015272.5 missense

Scores

1
5
10

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.72
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 Benign. Variant got -20 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.0074778795).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-53619093-G-C is Benign according to our data. Variant chr16-53619093-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 95693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-53619093-G-C is described in Lovd as [Benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00829 (1262/152290) while in subpopulation NFE AF= 0.0138 (941/68028). AF 95% confidence interval is 0.0131. There are 3 homozygotes in gnomad4. There are 555 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPGRIP1LNM_015272.5 linkuse as main transcriptc.3548C>G p.Ala1183Gly missense_variant 24/27 ENST00000647211.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPGRIP1LENST00000647211.2 linkuse as main transcriptc.3548C>G p.Ala1183Gly missense_variant 24/27 NM_015272.5 Q68CZ1-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00830
AC:
1263
AN:
152172
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00167
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00812
Gnomad ASJ
AF:
0.0130
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00352
Gnomad FIN
AF:
0.00405
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0138
Gnomad OTH
AF:
0.0110
GnomAD3 exomes
AF:
0.00968
AC:
2434
AN:
251490
Hom.:
16
AF XY:
0.00984
AC XY:
1338
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00185
Gnomad AMR exome
AF:
0.00364
Gnomad ASJ exome
AF:
0.0173
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00356
Gnomad FIN exome
AF:
0.00591
Gnomad NFE exome
AF:
0.0157
Gnomad OTH exome
AF:
0.0138
GnomAD4 exome
AF:
0.0118
AC:
17208
AN:
1461688
Hom.:
120
Cov.:
31
AF XY:
0.0116
AC XY:
8411
AN XY:
727152
show subpopulations
Gnomad4 AFR exome
AF:
0.00152
Gnomad4 AMR exome
AF:
0.00398
Gnomad4 ASJ exome
AF:
0.0164
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00335
Gnomad4 FIN exome
AF:
0.00605
Gnomad4 NFE exome
AF:
0.0137
Gnomad4 OTH exome
AF:
0.0108
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00829
AC:
1262
AN:
152290
Hom.:
3
Cov.:
32
AF XY:
0.00745
AC XY:
555
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00166
Gnomad4 AMR
AF:
0.00811
Gnomad4 ASJ
AF:
0.0130
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00352
Gnomad4 FIN
AF:
0.00405
Gnomad4 NFE
AF:
0.0138
Gnomad4 OTH
AF:
0.0109
Alfa
AF:
0.0138
Hom.:
10
Bravo
AF:
0.00832
TwinsUK
AF:
0.0135
AC:
50
ALSPAC
AF:
0.0109
AC:
42
ESP6500AA
AF:
0.00227
AC:
10
ESP6500EA
AF:
0.0153
AC:
132
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0103
AC:
1256
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.0130
EpiControl
AF:
0.0130

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 15, 2014This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 10, 2021- -
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 22, 2013- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 05, 2013- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided Benign:2
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024RPGRIP1L: BP4, BS1, BS2 -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Joubert syndrome 7 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Meckel syndrome, type 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Nephronophthisis 8 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Familial aplasia of the vermis Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.22
Cadd
Benign
22
Dann
Uncertain
0.99
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;.;D;D;D;D
MetaRNN
Benign
0.0075
T;T;T;T;T;T
MetaSVM
Benign
-0.47
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-2.0
N;.;.;N;N;N
REVEL
Benign
0.27
Sift
Uncertain
0.029
D;.;.;T;T;D
Sift4G
Benign
0.15
T;.;T;D;D;T
Polyphen
0.99
D;D;.;D;.;.
Vest4
0.38
MPC
0.073
ClinPred
0.035
T
GERP RS
5.9
Varity_R
0.17
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs139974543; hg19: chr16-53653005; COSMIC: COSV50908249; API