rs4784319

Variant names:

• chr16-53602021-A-T
• rs4784319
• NM_015272.5:c.*55T>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.*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
• Publications: 15 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 (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 VariationId 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 rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.*55T>A		3_prime_UTR_variant	Exon 27 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.*55T>A		3_prime_UTR_variant	Exon 27 of 27		NM_015272.5	ENSP00000493946.1

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

African (AFR) AF: 0.601 AC: 12452 AN: 20718

American (AMR) AF: 0.226 AC: 9192 AN: 40728

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 8285 AN: 21910

East Asian (EAS) AF: 0.547 AC: 19352 AN: 35352

South Asian (SAS) AF: 0.428 AC: 30632 AN: 71502

European-Finnish (FIN) AF: 0.183 AC: 9342 AN: 51148

Middle Eastern (MID) AF: 0.445 AC: 1983 AN: 4458

European-Non Finnish (NFE) AF: 0.278 AC: 157494 AN: 566118

Other (OTH) AF: 0.344 AC: 13731 AN: 39930

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

African (AFR) AF: 0.598 AC: 24805 AN: 41472

American (AMR) AF: 0.287 AC: 4387 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3470

East Asian (EAS) AF: 0.585 AC: 3015 AN: 5154

South Asian (SAS) AF: 0.428 AC: 2060 AN: 4814

European-Finnish (FIN) AF: 0.178 AC: 1881 AN: 10594

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.287 AC: 19495 AN: 67964

Other (OTH) AF: 0.385 AC: 813 AN: 2112

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

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.69
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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