Genetic Variant RPGRIP1L:c.3295-9_3295-8dupTT (chr16-53622363-C-CAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015272.5(RPGRIP1L):c.3295-9_3295-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 439,200 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000091 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0020 ( 0 hom. )

Consequence

RPGRIP1L
NM_015272.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.196

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5 link	c.3295-9_3295-8dupTT		splice_region_variant, intron_variant	Intron 22 of 26	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2 link	c.3295-8_3295-7insTT		splice_region_variant, intron_variant	Intron 22 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes

AF:

0.0000911

AC:

AN:

98822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000221

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000386

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000215

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00410

AC:

110

AN:

26824

AF XY:

0.00373

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.00414

Gnomad ASJ exome

AF:

0.00430

Gnomad EAS exome

AF:

0.00664

Gnomad FIN exome

AF:

0.00182

Gnomad NFE exome

AF:

0.00369

Gnomad OTH exome

AF:

0.00512

GnomAD4 exome

AF:

0.00199

AC:

676

AN:

340378

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

376

AN XY:

178448

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00301

AC:

AN:

9316

American (AMR)

AF:

0.00286

AC:

AN:

17458

Ashkenazi Jewish (ASJ)

AF:

0.00232

AC:

AN:

12050

East Asian (EAS)

AF:

0.000905

AC:

AN:

24298

South Asian (SAS)

AF:

0.00402

AC:

112

AN:

27880

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

22372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1560

European-Non Finnish (NFE)

AF:

0.00182

AC:

374

AN:

204934

Other (OTH)

AF:

0.00180

AC:

AN:

20510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.276

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000911

AC:

AN:

98822

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

AN XY:

46800

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000147

AC:

AN:

27206

American (AMR)

AF:

0.000221

AC:

AN:

9032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2464

East Asian (EAS)

AF:

0.00

AC:

AN:

3376

South Asian (SAS)

AF:

0.00

AC:

AN:

3080

European-Finnish (FIN)

AF:

0.000386

AC:

AN:

5186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.0000215

AC:

AN:

46438

Other (OTH)

AF:

0.00

AC:

AN:

1304

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000282722), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.20

Splicing

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

Publications

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16-53622363-CAAAAAA-CAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over