chr16-53602021-A-T

Position:

• chr16-53602021-A-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.*55T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,003,926 control chromosomes in the GnomAD database, including 57,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12810 hom., cov: 32)
  • Exomes 𝑓: 0.31 (44733 hom.)
• Consequence: RPGRIP1L NM_015272.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.401

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 (BayesDel_noAF=-0.88).
• BP6: Variant 16-53602021-A-T is Benign according to our data. Variant chr16-53602021-A-T is described in ClinVar as [Benign]. Clinvar id is 319645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.*55T>A		3_prime_UTR_variant	27/27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.*55T>A		3_prime_UTR_variant	27/27		NM_015272.5	ENSP00000493946

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57861 AN: 151944 Hom.: 12770 Cov.: 32

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.308 AC: 262463 AN: 851864 Hom.: 44733 Cov.: 11 AF XY: 0.314 AC XY: 139949 AN XY: 445450

Gnomad4 AFR exome AF: 0.601

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.378

Gnomad4 EAS exome AF: 0.547

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.344

GnomAD4 genome AF: 0.381 AC: 57959 AN: 152062 Hom.: 12810 Cov.: 32 AF XY: 0.376 AC XY: 27976 AN XY: 74310

Gnomad4 AFR AF: 0.598

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.585

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.385

Alfa AF: 0.331 Hom.: 1178

Bravo AF: 0.395

Asia WGS AF: 0.510 AC: 1777 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.69

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: rs4784319; hg19: chr16-53635933; COSMIC: COSV50903475; COSMIC: COSV50903475;