rs201808974

Variant names:

• chr16-53673045-CATT-C
• rs201808974
• NM_015272.5:c.883-32_883-30delAAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015272.5(RPGRIP1L):​c.883-32_883-30delAAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,594,690 control chromosomes in the GnomAD database, including 79 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (68 hom.)
• Consequence: RPGRIP1L NM_015272.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.612
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 16-53673045-CATT-C is Benign according to our data. Variant chr16-53673045-CATT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 260612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00714 (1087/152246) while in subpopulation NFE AF = 0.00768 (522/67996). AF 95% confidence interval is 0.00713. There are 11 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.883-32_883-30delAAT		intron_variant	Intron 7 of 26	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.883-32_883-30delAAT		intron_variant	Intron 7 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.00716 AC: 1089 AN: 152128 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00768

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00783 AC: 1871 AN: 238842 AF XY: 0.00817

Gnomad AFR exome AF: 0.000401

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.00748

Gnomad OTH exome AF: 0.00873

GnomAD4 exome AF: 0.00625 AC: 9022 AN: 1442444 Hom.: 68 AF XY: 0.00648 AC XY: 4650 AN XY: 718122

African (AFR) AF: 0.000604 AC: 20 AN: 33136

American (AMR) AF: 0.00383 AC: 169 AN: 44096

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 397 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.00367 AC: 313 AN: 85264

European-Finnish (FIN) AF: 0.0309 AC: 1589 AN: 51486

Middle Eastern (MID) AF: 0.00439 AC: 22 AN: 5006

European-Non Finnish (NFE) AF: 0.00559 AC: 6137 AN: 1098524

Other (OTH) AF: 0.00629 AC: 375 AN: 59608

GnomAD4 genome AF: 0.00714 AC: 1087 AN: 152246 Hom.: 11 Cov.: 32 AF XY: 0.00834 AC XY: 621 AN XY: 74440

African (AFR) AF: 0.000794 AC: 33 AN: 41558

American (AMR) AF: 0.00582 AC: 89 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0337 AC: 357 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00768 AC: 522 AN: 67996

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00891 Hom.: 2

Bravo AF: 0.00474

Asia WGS AF: 0.00145 AC: 5 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 28, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201808974; hg19: chr16-53706957;