chr16-53671580-G-A

Variant names:

• chr16-53671580-G-A
• rs121918202
• NM_015272.5:c.1033C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015272.5(RPGRIP1L):​c.1033C>T​(p.Gln345*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q345Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPGRIP1L NM_015272.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.03
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-53671580-G-A is Pathogenic according to our data. Variant chr16-53671580-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1073.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.1033C>T	p.Gln345*	stop_gained	Exon 9 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.1033C>T	p.Gln345*	stop_gained	Exon 9 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1349176 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 676104

African (AFR) AF: 0.00 AC: 0 AN: 31234

American (AMR) AF: 0.00 AC: 0 AN: 43788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 38794

South Asian (SAS) AF: 0.00 AC: 0 AN: 80958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1016492

Other (OTH) AF: 0.00 AC: 0 AN: 56476

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Meckel syndrome, type 5 Pathogenic:1

Jul 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jan 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln345*) in the RPGRIP1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGRIP1L are known to be pathogenic (PMID: 17558409). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with RPGRIP1L-related conditions (PMID: 17558409). ClinVar contains an entry for this variant (Variation ID: 1073). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.0
Vest4		0.75
GERP RS		5.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.10		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: rs121918202; hg19: chr16-53705492;