NM_015272.5:c.530-29G>A

Variant names:

• chr16-53687994-C-T
• rs74393433
• NM_015272.5:c.530-29G>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.530-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,295,766 control chromosomes in the GnomAD database, including 3,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.053 (407 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3405 hom.)
• Consequence: RPGRIP1L NM_015272.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.984
• Publications: 6 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-53687994-C-T is Benign according to our data. Variant chr16-53687994-C-T is described in ClinVar as Benign. ClinVar VariationId is 126281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.530-29G>A		intron	N/A	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.530-29G>A		intron	N/A	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.530-29G>A		intron	N/A	NP_001295263.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.530-29G>A		intron	N/A	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.530-29G>A		intron	N/A	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.530-29G>A		intron	N/A	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8124 AN: 151806 Hom.: 407 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0525

Gnomad ASJ AF: 0.0572

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.0565

GnomAD2 exomes AF: 0.0736 AC: 18274 AN: 248406 AF XY: 0.0717

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.0676

Gnomad ASJ exome AF: 0.0609

Gnomad EAS exome AF: 0.315

Gnomad FIN exome AF: 0.0443

Gnomad NFE exome AF: 0.0528

Gnomad OTH exome AF: 0.0629

GnomAD4 exome AF: 0.0612 AC: 69950 AN: 1143842 Hom.: 3405 Cov.: 15 AF XY: 0.0612 AC XY: 35721 AN XY: 583990

African (AFR) AF: 0.0169 AC: 460 AN: 27144

American (AMR) AF: 0.0645 AC: 2847 AN: 44166

Ashkenazi Jewish (ASJ) AF: 0.0586 AC: 1409 AN: 24030

East Asian (EAS) AF: 0.273 AC: 10391 AN: 38024

South Asian (SAS) AF: 0.0683 AC: 5389 AN: 78868

European-Finnish (FIN) AF: 0.0457 AC: 2417 AN: 52912

Middle Eastern (MID) AF: 0.0289 AC: 129 AN: 4468

European-Non Finnish (NFE) AF: 0.0527 AC: 43450 AN: 824436

Other (OTH) AF: 0.0694 AC: 3458 AN: 49794

GnomAD4 genome AF: 0.0535 AC: 8127 AN: 151924 Hom.: 407 Cov.: 32 AF XY: 0.0543 AC XY: 4031 AN XY: 74266

African (AFR) AF: 0.0212 AC: 880 AN: 41480

American (AMR) AF: 0.0528 AC: 806 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0572 AC: 198 AN: 3464

East Asian (EAS) AF: 0.304 AC: 1569 AN: 5164

South Asian (SAS) AF: 0.0765 AC: 369 AN: 4826

European-Finnish (FIN) AF: 0.0419 AC: 442 AN: 10546

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0543 AC: 3687 AN: 67866

Other (OTH) AF: 0.0583 AC: 123 AN: 2110

Alfa AF: 0.0497 Hom.: 55

Bravo AF: 0.0545

Asia WGS AF: 0.191 AC: 662 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joubert syndrome 7 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Meckel syndrome, type 5 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.061
DANN	Benign	0.38
PhyloP100		-0.98
BranchPoint Hunter		0.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74393433; hg19: chr16-53721906;