NM_015272.5:c.2959-32G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015272.5(RPGRIP1L):c.2959-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,132,226 control chromosomes in the GnomAD database, including 66,730 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 0.39 ( 13699 hom., cov: 32)

Exomes 𝑓: 0.31 ( 53031 hom. )

Consequence

RPGRIP1L
NM_015272.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0300

Publications

18 publications found

Variant links:

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

RPGRIP1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=-0.88).

BP6

Variant 16-53638443-C-T is Benign according to our data. Variant chr16-53638443-C-T is described in ClinVar as Benign. ClinVar VariationId is 126276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5 link	c.2959-32G>A		intron_variant	Intron 19 of 26	ENST00000647211.2	NP_056087.2	Q68CZ1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2 link	c.2959-32G>A		intron_variant	Intron 19 of 26		NM_015272.5	ENSP00000493946.1		Q68CZ1-1

Frequencies

GnomAD3 genomes

AF:

0.393

AC:

59571

AN:

151608

Hom.:

13650

Cov.:

show subpopulations

Gnomad AFR

AF:

0.625

Gnomad AMI

AF:

0.227

Gnomad AMR

AF:

0.300

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.587

Gnomad SAS

AF:

0.410

Gnomad FIN

AF:

0.179

Gnomad MID

AF:

0.503

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.397

GnomAD2 exomes

AF:

0.339

AC:

82446

AN:

243214

AF XY:

0.340

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.226

Gnomad ASJ exome

AF:

0.406

Gnomad EAS exome

AF:

0.603

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.294

Gnomad OTH exome

AF:

0.341

GnomAD4 exome

AF:

0.311

AC:

305082

AN:

980502

Hom.:

53031

Cov.:

AF XY:

0.316

AC XY:

160478

AN XY:

508266

show subpopulations

African (AFR)

AF:

0.636

AC:

15214

AN:

23908

American (AMR)

AF:

0.230

AC:

10029

AN:

43546

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

9233

AN:

23030

East Asian (EAS)

AF:

0.551

AC:

20472

AN:

37172

South Asian (SAS)

AF:

0.407

AC:

30791

AN:

75662

European-Finnish (FIN)

AF:

0.186

AC:

9652

AN:

51968

Middle Eastern (MID)

AF:

0.499

AC:

2396

AN:

4798

European-Non Finnish (NFE)

AF:

0.283

AC:

191601

AN:

675878

Other (OTH)

AF:

0.352

AC:

15694

AN:

44540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

9395

18791

28186

37582

46977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4966

9932

14898

19864

24830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.393

AC:

59678

AN:

151724

Hom.:

13699

Cov.:

AF XY:

0.388

AC XY:

28798

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.626

AC:

25917

AN:

41414

American (AMR)

AF:

0.299

AC:

4561

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

1265

AN:

3458

East Asian (EAS)

AF:

0.587

AC:

3028

AN:

5162

South Asian (SAS)

AF:

0.410

AC:

1975

AN:

4818

European-Finnish (FIN)

AF:

0.179

AC:

1883

AN:

10526

Middle Eastern (MID)

AF:

0.500

AC:

146

AN:

292

European-Non Finnish (NFE)

AF:

0.293

AC:

19843

AN:

67798

Other (OTH)

AF:

0.404

AC:

853

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1674

3348

5022

6696

8370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

562

1124

1686

2248

2810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.357

Hom.:

3856

Bravo

AF:

0.409

Asia WGS

AF:

0.500

AC:

1737

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

- -

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

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: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

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

8.7

(source)

DANN

Benign

0.39

PhyloP100

-0.030

BranchPoint Hunter

0.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over