16-53622363-CAAAAAA-CAAAAA

Variant names:

• chr16-53622363-CA-C
• rs113083177
• NM_015272.5:c.3295-8delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_015272.5(RPGRIP1L):​c.3295-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (21 hom., cov: 30)
  • Exomes 𝑓: 0.30 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPGRIP1L NM_015272.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.196
• Publications: 2 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 -8 ACMG points.

• BP6: Variant 16-53622363-CA-C is Benign according to our data. Variant chr16-53622363-CA-C is described in ClinVar as Benign. ClinVar VariationId is 126278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3295-8delT		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	c.3295-8delT		splice_region_variant, intron_variant	Intron 22 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 1921 AN: 98546 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00366

Gnomad EAS AF: 0.00267

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.0172

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.352 AC: 9430 AN: 26824 AF XY: 0.352

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.305 AC: 93755 AN: 307486 Hom.: 1 Cov.: 0 AF XY: 0.304 AC XY: 49077 AN XY: 161458

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

African (AFR) AF: 0.305 AC: 2570 AN: 8438

American (AMR) AF: 0.304 AC: 4992 AN: 16446

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 3334 AN: 10908

East Asian (EAS) AF: 0.314 AC: 6549 AN: 20864

South Asian (SAS) AF: 0.284 AC: 7650 AN: 26940

European-Finnish (FIN) AF: 0.312 AC: 6209 AN: 19910

Middle Eastern (MID) AF: 0.296 AC: 409 AN: 1384

European-Non Finnish (NFE) AF: 0.306 AC: 56330 AN: 184038

Other (OTH) AF: 0.308 AC: 5712 AN: 18558

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0196 AC: 1928 AN: 98582 Hom.: 21 Cov.: 30 AF XY: 0.0202 AC XY: 942 AN XY: 46704

African (AFR) AF: 0.0495 AC: 1348 AN: 27232

American (AMR) AF: 0.0136 AC: 123 AN: 9020

Ashkenazi Jewish (ASJ) AF: 0.00366 AC: 9 AN: 2456

East Asian (EAS) AF: 0.00267 AC: 9 AN: 3366

South Asian (SAS) AF: 0.00229 AC: 7 AN: 3062

European-Finnish (FIN) AF: 0.0324 AC: 165 AN: 5098

Middle Eastern (MID) AF: 0.0183 AC: 3 AN: 164

European-Non Finnish (NFE) AF: 0.00510 AC: 236 AN: 46312

Other (OTH) AF: 0.0214 AC: 28 AN: 1310

Alfa AF: 0.000388 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 18, 2014

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Kidney disorder Benign:1

Mar 27, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1

Nov 14, 2022

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
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs113083177; hg19: chr16-53656275;