16-53622223-G-C

Variant names:

• chr16-53622223-G-C
• rs111775292
• NM_015272.5:c.3428C>G

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.3428C>G​(p.Thr1143Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 661,030 control chromosomes in the GnomAD database, including 6,724 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1579 hom., cov: 28)
  • Exomes 𝑓: 0.14 (5145 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.252

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=0.001986444).
• BP6: Variant 16-53622223-G-C is Benign according to our data. Variant chr16-53622223-G-C is described in ClinVar as [Benign]. Clinvar id is 95692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-53622223-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3428C>G	p.Thr1143Ser	missense_variant	Exon 23 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.3428C>G	p.Thr1143Ser	missense_variant	Exon 23 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21487 AN: 151032 Hom.: 1577 Cov.: 28

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.122 AC: 12371 AN: 101682 Hom.: 880 AF XY: 0.124 AC XY: 6975 AN XY: 56274

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0813

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.108

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.136 AC: 69476 AN: 509880 Hom.: 5145 Cov.: 0 AF XY: 0.137 AC XY: 37737 AN XY: 275208

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.0827

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.142 AC: 21487 AN: 151150 Hom.: 1579 Cov.: 28 AF XY: 0.140 AC XY: 10362 AN XY: 73784

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.150

Alfa AF: 0.143 Hom.: 275

Bravo AF: 0.140

TwinsUK AF: 0.133 AC: 495

ALSPAC AF: 0.135 AC: 522

ExAC AF: 0.107 AC: 1474

Asia WGS AF: 0.111 AC: 387 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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. -

Aug 09, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Jan 12, 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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 5 Benign:2

Jan 12, 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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.42
DANN	Benign	0.11
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0038	N
LIST_S2	Benign	0.093	.;T;T
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.26	.;N;N
REVEL	Benign	0.038
Sift	Benign	0.76	.;T;T
Sift4G	Benign	0.95	.;T;T
Polyphen		0.0050	B;B;.
Vest4		0.028, 0.0080
MutPred		0.28		Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);.;
MPC		0.065
ClinPred		0.0015	T
GERP RS		0.16
Varity_R		0.060
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: rs111775292; hg19: chr16-53656135;