rs2111119

Variant names:

• chr16-53637842-C-T
• rs2111119
• NM_015272.5:c.3073G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015272.5(RPGRIP1L):​c.3073G>A​(p.Gly1025Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,611,706 control chromosomes in the GnomAD database, including 9,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1140 hom., cov: 32)
  • Exomes 𝑓: 0.095 (8103 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.51
• Publications: 37 publications found

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]

RPGRIP1L Gene-Disease associations (from GenCC):

• Meckel syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Joubert syndrome 7

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with renal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004034281).
• BP6: Variant 16-53637842-C-T is Benign according to our data. Variant chr16-53637842-C-T is described in ClinVar as Benign. ClinVar VariationId is 126277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3073G>A	p.Gly1025Ser	missense_variant	Exon 21 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.3073G>A	p.Gly1025Ser	missense_variant	Exon 21 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16938 AN: 151960 Hom.: 1134 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0835

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.112 AC: 28086 AN: 250566 AF XY: 0.110

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.0904

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0809

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0954 AC: 139258 AN: 1459628 Hom.: 8103 Cov.: 32 AF XY: 0.0961 AC XY: 69800 AN XY: 726206

African (AFR) AF: 0.155 AC: 5191 AN: 33404

American (AMR) AF: 0.0886 AC: 3960 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3756 AN: 26102

East Asian (EAS) AF: 0.280 AC: 11098 AN: 39592

South Asian (SAS) AF: 0.137 AC: 11842 AN: 86212

European-Finnish (FIN) AF: 0.0550 AC: 2904 AN: 52842

Middle Eastern (MID) AF: 0.110 AC: 633 AN: 5758

European-Non Finnish (NFE) AF: 0.0838 AC: 93104 AN: 1110730

Other (OTH) AF: 0.112 AC: 6770 AN: 60310

GnomAD4 genome AF: 0.112 AC: 16959 AN: 152078 Hom.: 1140 Cov.: 32 AF XY: 0.110 AC XY: 8162 AN XY: 74310

African (AFR) AF: 0.158 AC: 6545 AN: 41478

American (AMR) AF: 0.0838 AC: 1280 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 470 AN: 3462

East Asian (EAS) AF: 0.309 AC: 1594 AN: 5158

South Asian (SAS) AF: 0.143 AC: 689 AN: 4822

European-Finnish (FIN) AF: 0.0482 AC: 510 AN: 10584

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0812 AC: 5519 AN: 67982

Other (OTH) AF: 0.122 AC: 258 AN: 2116

Alfa AF: 0.0972 Hom.: 3979

Bravo AF: 0.117

TwinsUK AF: 0.0806 AC: 299

ALSPAC AF: 0.0851 AC: 328

ESP6500AA AF: 0.157 AC: 688

ESP6500EA AF: 0.0865 AC: 744

ExAC AF: 0.114 AC: 13893

Asia WGS AF: 0.232 AC: 804 AN: 3476

EpiCase AF: 0.0855

EpiControl AF: 0.0860

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Joubert syndrome 7 Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Meckel syndrome, type 5 Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Joubert syndrome Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nephronophthisis 8 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.19
DEOGEN2	Benign	0.0021	.;.;T;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.13	T;.;T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	.;N;.;N;.;.
PhyloP100		1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	N;.;.;N;N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;.;.;T;T;T
Sift4G	Benign	0.82	T;.;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.
Vest4		0.029
MPC		0.072
ClinPred		0.00058	T
GERP RS		3.0
Varity_R		0.030
gMVP		0.12
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2111119; hg19: chr16-53671754; COSMIC: COSV50903572;