chr16-53622350-C-CGA

Variant names:

• chr16-53622350-C-CGA
• rs797045104
• NM_015272.5:c.3299_3300dupTC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_015272.5(RPGRIP1L):​c.3299_3300dupTC​(p.Ala1101SerfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 593,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L1100L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.834
• 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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-53622350-C-CGA is Pathogenic according to our data. Variant chr16-53622350-C-CGA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.3299_3300dupTC	p.Ala1101SerfsTer34	frameshift	Exon 23 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.3197_3198dupTC	p.Ala1067SerfsTer34	frameshift	Exon 22 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.3295-3144_3295-3143dupTC		intron	N/A	NP_001295263.1	A0A087WX34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.3299_3300dupTC	p.Ala1101SerfsTer34	frameshift	Exon 23 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.3197_3198dupTC	p.Ala1067SerfsTer34	frameshift	Exon 22 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3295-3144_3295-3143dupTC		intron	N/A	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.0000607 AC: 9 AN: 148374 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00177

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000274 AC: 2 AN: 73014 AF XY: 0.0000493

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000413

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 5 AN: 445172 Hom.: 0 Cov.: 0 AF XY: 0.0000168 AC XY: 4 AN XY: 237502

African (AFR) AF: 0.00 AC: 0 AN: 12250

American (AMR) AF: 0.00 AC: 0 AN: 26486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16974

East Asian (EAS) AF: 0.000177 AC: 5 AN: 28188

South Asian (SAS) AF: 0.00 AC: 0 AN: 44816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2072

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 260598

Other (OTH) AF: 0.00 AC: 0 AN: 25548

GnomAD4 genome AF: 0.0000606 AC: 9 AN: 148466 Hom.: 0 Cov.: 30 AF XY: 0.0000416 AC XY: 3 AN XY: 72164

African (AFR) AF: 0.00 AC: 0 AN: 40102

American (AMR) AF: 0.00 AC: 0 AN: 14780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00178 AC: 9 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67456

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome 7 (1)
1	-	-	Joubert syndrome and related disorders (1)
1	-	-	Meckel syndrome, type 5;C1969053:Joubert syndrome 7;C5436841:COACH syndrome 3 (1)
1	-	-	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
1	-	-	RPGRIP1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.83
Mutation Taster		=23/177	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045104; hg19: chr16-53656262;