16-53649028-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_015272.5(RPGRIP1L):c.2240G>A(p.Arg747Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,934 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R747R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

RPGRIP1L
NM_015272.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 1.38

Publications

15 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):

ciliopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019827366).

BP6

Variant 16-53649028-C-T is Benign according to our data. Variant chr16-53649028-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166909.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGRIP1L	NM_015272.5	MANE Select	c.2240G>A	p.Arg747Gln	missense	Exon 16 of 27	NP_056087.2	Q68CZ1-1
RPGRIP1L	NM_001330538.2		c.2240G>A	p.Arg747Gln	missense	Exon 16 of 26	NP_001317467.1	H3BV03
RPGRIP1L	NM_001308334.3		c.2240G>A	p.Arg747Gln	missense	Exon 16 of 26	NP_001295263.1	A0A087WX34

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGRIP1L	ENST00000647211.2	MANE Select	c.2240G>A	p.Arg747Gln	missense	Exon 16 of 27	ENSP00000493946.1	Q68CZ1-1
RPGRIP1L	ENST00000563746.5	TSL:1	c.2240G>A	p.Arg747Gln	missense	Exon 16 of 26	ENSP00000457889.1	H3BV03
RPGRIP1L	ENST00000621565.5	TSL:1	c.2240G>A	p.Arg747Gln	missense	Exon 16 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000740

AC:

186

AN:

251422

AF XY:

0.000648

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00126

AC:

1846

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

876

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33474

American (AMR)

AF:

0.000514

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000227

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00158

AC:

1759

AN:

1111826

Other (OTH)

AF:

0.000695

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

177

265

354

442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.000808

AC:

123

AN:

152272

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41560

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000578

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00151

AC:

103

AN:

68018

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00111

Hom.:

Bravo

AF:

0.000778

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000749

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Meckel syndrome, type 5 (2)

not provided (2)

Joubert syndrome (1)

Joubert syndrome 7 (1)

Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Nephronophthisis 8 (1)

RPGRIP1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.018

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.1

PhyloP100

1.4

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.97

REVEL

Benign

0.063

Sift

Benign

0.21

Sift4G

Benign

0.19

Polyphen

0.010

Vest4

0.12

MVP

0.47

MPC

0.093

ClinPred

0.015

GERP RS

3.1

Varity_R

0.084

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over