16-53658781-C-T

Variant names:

• chr16-53658781-C-T
• rs61743997
• NM_015272.5:c.1341G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015272.5(RPGRIP1L):​c.1341G>A​(p.Leu447Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,591,368 control chromosomes in the GnomAD database, including 502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (55 hom., cov: 32)
  • Exomes 𝑓: 0.022 (447 hom.)
• Consequence: RPGRIP1L NM_015272.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.31

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 16-53658781-C-T is Benign according to our data. Variant chr16-53658781-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 126275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-53658781-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0225 (3421/152252) while in subpopulation SAS AF= 0.0401 (194/4834). AF 95% confidence interval is 0.0355. There are 55 homozygotes in gnomad4. There are 1639 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.1341G>A	p.Leu447Leu	synonymous_variant	Exon 11 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.1341G>A	p.Leu447Leu	synonymous_variant	Exon 11 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3416 AN: 152134 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0218 AC: 5084 AN: 233538 Hom.: 87 AF XY: 0.0230 AC XY: 2900 AN XY: 125896

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00815

Gnomad SAS exome AF: 0.0439

Gnomad FIN exome AF: 0.00686

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0222 AC: 31941 AN: 1439116 Hom.: 447 Cov.: 28 AF XY: 0.0228 AC XY: 16291 AN XY: 715482

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.0400

Gnomad4 FIN exome AF: 0.00689

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.0225 AC: 3421 AN: 152252 Hom.: 55 Cov.: 32 AF XY: 0.0220 AC XY: 1639 AN XY: 74450

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0210

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.0401

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.0184 Hom.: 12

Bravo AF: 0.0230

Asia WGS AF: 0.0350 AC: 123 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 15, 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. -

-

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

- -

Joubert syndrome 7 Benign:2

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. -

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 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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

- -

Kidney disorder Benign:1

Mar 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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. -

Familial aplasia of the vermis Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	3.8
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61743997; hg19: chr16-53692693;