16-53638443-C-T

Variant names:

• chr16-53638443-C-T
• rs7203525
• NM_015272.5:c.2959-32G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015272.5(RPGRIP1L):​c.2959-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,132,226 control chromosomes in the GnomAD database, including 66,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.39 (13699 hom., cov: 32)
  • Exomes 𝑓: 0.31 (53031 hom.)
• Consequence: RPGRIP1L NM_015272.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0300

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 Benign. Variant got -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-53638443-C-T is Benign according to our data. Variant chr16-53638443-C-T is described in ClinVar as [Benign]. Clinvar id is 126276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.2959-32G>A		intron_variant	Intron 19 of 26	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.2959-32G>A		intron_variant	Intron 19 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59571 AN: 151608 Hom.: 13650 Cov.: 32

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.397

GnomAD3 exomes AF: 0.339 AC: 82446 AN: 243214 Hom.: 16138 AF XY: 0.340 AC XY: 44760 AN XY: 131710

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.603

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.311 AC: 305082 AN: 980502 Hom.: 53031 Cov.: 13 AF XY: 0.316 AC XY: 160478 AN XY: 508266

Gnomad4 AFR exome AF: 0.636

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.551

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.283

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.393 AC: 59678 AN: 151724 Hom.: 13699 Cov.: 32 AF XY: 0.388 AC XY: 28798 AN XY: 74164

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.299

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.587

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.404

Alfa AF: 0.346 Hom.: 3274

Bravo AF: 0.409

Asia WGS AF: 0.500 AC: 1737 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 7 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 5 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.7
DANN	Benign	0.39
BranchPoint Hunter		0.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs7203525; hg19: chr16-53672355; COSMIC: COSV50902765; COSMIC: COSV50902765;