rs121918200

chr16-53652604-C-Gchr16-53652604-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_015272.5(RPGRIP1L):c.2083G>C(p.Ala695Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A695K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.863

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 16-53652604-C-G is Pathogenic according to our data. Variant chr16-53652604-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1071.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1L	NM_015272.5	c.2083G>C	p.Ala695Pro	missense_variant	15/27	ENST00000647211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.2083G>C	p.Ala695Pro	missense_variant	15/27		NM_015272.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Joubert syndrome 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D;.;D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.4	M;M;.;M;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.4	D;.;.;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.023	D;.;.;D;D;D
Sift4G	Uncertain	0.039	D;.;D;D;D;D
Polyphen		0.99	D;D;.;D;.;.
Vest4		0.86
MutPred		0.79		Gain of catalytic residue at A695 (P = 0.0748);Gain of catalytic residue at A695 (P = 0.0748);Gain of catalytic residue at A695 (P = 0.0748);Gain of catalytic residue at A695 (P = 0.0748);Gain of catalytic residue at A695 (P = 0.0748);Gain of catalytic residue at A695 (P = 0.0748);
MVP		0.85
MPC		0.38
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.69
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs121918200; hg19: chr16-53686516;