rs2111119

Positions:

• chr16-53637842-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.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. 15/20 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:10
• Conservation: PhyloP100: 1.51

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=0.004034281).
• BP6: Variant 16-53637842-C-T is Benign according to our data. Variant chr16-53637842-C-T is described in ClinVar as [Benign]. Clinvar id is 126277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-53637842-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
RPGRIP1L	NM_015272.5	c.3073G>A	p.Gly1025Ser	missense_variant	21/27	ENST00000647211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.3073G>A	p.Gly1025Ser	missense_variant	21/27		NM_015272.5

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

GnomAD3 exomes AF: 0.112 AC: 28086 AN: 250566 Hom.: 2107 AF XY: 0.110 AC XY: 14940 AN XY: 135442

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 SAS exome AF: 0.135

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

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.0886

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.280

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.0550

Gnomad4 NFE exome AF: 0.0838

Gnomad4 OTH exome AF: 0.112

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

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.0838

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.309

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0482

Gnomad4 NFE AF: 0.0812

Gnomad4 OTH AF: 0.122

Alfa AF: 0.0950 Hom.: 2039

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 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. -
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. -

Joubert syndrome 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Meckel syndrome, type 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Nephronophthisis 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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
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
MutationTaster	Benign	1.0	P;P;P;P
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

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