16-53622363-CAAAAAA-CAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_015272.5(RPGRIP1L):​c.3295-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0661 in 429,872 control chromosomes in the GnomAD database, including 17 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 30)
  • Exomes 𝑓: 0.082 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1274/98650) while in subpopulation AFR AF = 0.0354 (964/27222). AF 95% confidence interval is 0.0336. There are 17 homozygotes in GnomAd4. There are 607 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.3295-8dupT		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.3295-8_3295-7insT		splice_region_variant, intron_variant	Intron 22 of 26		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1264 AN: 98608 Hom.: 16 Cov.: 30

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.00122

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00325

Gnomad FIN AF: 0.00955

Gnomad MID AF: 0.0230

Gnomad NFE AF: 0.00302

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0827 AC: 2219 AN: 26824 AF XY: 0.0815

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0925

Gnomad ASJ exome AF: 0.0995

Gnomad EAS exome AF: 0.0959

Gnomad FIN exome AF: 0.0545

Gnomad NFE exome AF: 0.0668

Gnomad OTH exome AF: 0.0921

GnomAD4 exome AF: 0.0819 AC: 27140 AN: 331222 Hom.: 0 Cov.: 0 AF XY: 0.0816 AC XY: 14171 AN XY: 173740

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

African (AFR) AF: 0.0955 AC: 871 AN: 9116

American (AMR) AF: 0.0840 AC: 1440 AN: 17134

Ashkenazi Jewish (ASJ) AF: 0.0823 AC: 964 AN: 11712

East Asian (EAS) AF: 0.0792 AC: 1855 AN: 23414

South Asian (SAS) AF: 0.0869 AC: 2390 AN: 27516

European-Finnish (FIN) AF: 0.0756 AC: 1635 AN: 21628

Middle Eastern (MID) AF: 0.0851 AC: 128 AN: 1504

European-Non Finnish (NFE) AF: 0.0813 AC: 16207 AN: 199258

Other (OTH) AF: 0.0827 AC: 1650 AN: 19940

⚠️ 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 AF: 0.0129 AC: 1274 AN: 98650 Hom.: 17 Cov.: 30 AF XY: 0.0130 AC XY: 607 AN XY: 46756

African (AFR) AF: 0.0354 AC: 964 AN: 27222

American (AMR) AF: 0.00809 AC: 73 AN: 9026

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 3 AN: 2460

East Asian (EAS) AF: 0.00386 AC: 13 AN: 3368

South Asian (SAS) AF: 0.00359 AC: 11 AN: 3062

European-Finnish (FIN) AF: 0.00955 AC: 49 AN: 5132

Middle Eastern (MID) AF: 0.0366 AC: 6 AN: 164

European-Non Finnish (NFE) AF: 0.00302 AC: 140 AN: 46342

Other (OTH) AF: 0.0114 AC: 15 AN: 1312

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

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)		0.060		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;