rs61747071

chr16-53686524-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015272.5(RPGRIP1L):c.685G>A(p.Ala229Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,613,474 control chromosomes in the GnomAD database, including 1,418 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (293 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1125 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:15 O:3
• Conservation: PhyloP100: -0.0220

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004353553).
• BP6: Variant 16-53686524-C-T is Benign according to our data. Variant chr16-53686524-C-T is described in ClinVar as [Benign]. Clinvar id is 1078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-53686524-C-T is described in Lovd as [Benign]. Variant chr16-53686524-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1L	NM_015272.5	c.685G>A	p.Ala229Thr	missense_variant	6/27	ENST00000647211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.685G>A	p.Ala229Thr	missense_variant	6/27		NM_015272.5

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7441 AN: 152014 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0794

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0657

Gnomad FIN AF: 0.00698

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0576

GnomAD3 exomes AF: 0.0356 AC: 8949 AN: 251116 Hom.: 245 AF XY: 0.0363 AC XY: 4923 AN XY: 135708

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0841

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0678

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0325 AC: 47508 AN: 1461340 Hom.: 1125 Cov.: 31 AF XY: 0.0333 AC XY: 24235 AN XY: 726978

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0843

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0680

Gnomad4 FIN exome AF: 0.00927

Gnomad4 NFE exome AF: 0.0284

Gnomad4 OTH exome AF: 0.0379

GnomAD4 genome AF: 0.0490 AC: 7448 AN: 152134 Hom.: 293 Cov.: 32 AF XY: 0.0470 AC XY: 3497 AN XY: 74392

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0794

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0666

Gnomad4 FIN AF: 0.00698

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0570

Alfa AF: 0.0395 Hom.: 107

Bravo AF: 0.0519

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0296 AC: 114

ESP6500AA AF: 0.101 AC: 443

ESP6500EA AF: 0.0328 AC: 282

ExAC AF: 0.0374 AC: 4547

Asia WGS AF: 0.0360 AC: 125 AN: 3476

EpiCase AF: 0.0334

EpiControl AF: 0.0349

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:15 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2014	This 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2021	Variant summary: RPGRIP1L c.685G>A (p.Ala229Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.036 in 251116 control chromosomes, predominantly at a frequency of 0.11 within the African or African-American subpopulation in the gnomAD database, including 73 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 139.14 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGRIP1L causing Joubert Syndrome And Related Disorders phenotype (0.00079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign. -

Joubert syndrome 7 Benign:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial aplasia of the vermis Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	curation	GeneReviews	Mar 29, 2012	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Meckel syndrome, type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 09, 2022

- -

Nephronophthisis 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Retinitis pigmentosa in ciliopathies, modifier of Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Benign	0.97
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.77	T;.;T;T;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.;N;.;.;.
MutationTaster	Benign	0.0055	A;A;A;A
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.010	N;.;.;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.47	T;.;.;T;T;T;T
Sift4G	Benign	0.61	T;.;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.;.
Vest4		0.074
MPC		0.070
ClinPred		0.0045	T
GERP RS		2.7
Varity_R		0.054
gMVP		0.19

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

Other links and lift over

dbSNP: rs61747071; hg19: chr16-53720436;