rs751527253

Positions:

• chr3-132689263-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153240.5(NPHP3):​c.2694-2_2694-1delAG variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: NPHP3 NM_153240.5 splice_acceptor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 7.47

Genes affected

NPHP3 (HGNC:7907): (nephrocystin 3) This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]

NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

NPHP3 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-132689263-CCT-C is Pathogenic according to our data. Variant chr3-132689263-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132689263-CCT-C is described in Lovd as [Pathogenic]. Variant chr3-132689263-CCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.2694-2_2694-1delAG		splice_acceptor_variant, intron_variant		ENST00000337331.10	NP_694972.3
NPHP3-ACAD11	NR_037804.1	n.2700-2_2700-1delAG		splice_acceptor_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.2694-2_2694-1delAG		splice_acceptor_variant, intron_variant		1	NM_153240.5	ENSP00000338766.5

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 251300 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135854

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000235 AC: 343 AN: 1461704 Hom.: 0 AF XY: 0.000245 AC XY: 178 AN XY: 727158

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74460

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000538 Hom.: 0

Bravo AF: 0.000257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Likely pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	NPHP3: PVS1, PS3:Supporting, PS4:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2022	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate this variant leads to loss of splice acceptor resulting in skipping of exon 20 (Molinari et al., 2018); This variant is associated with the following publications: (PMID: 27894351, 28973083, 30002499, 34426522, 32055034, 31980526, 32552793, 32901917, 20007846, 18371931, 33726816, 27535533) -

Nephronophthisis 3 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 15, 2018	The heterozygous c.2694-2_2694-1delAG variant was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nephronophthisis. This variant is pathogenic based off of multiple reports in ClinVar and the literature. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Precision Medicine Center, Zhengzhou University	Dec 01, 2023	PVS1,PM2_p -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0002759, PM2).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000220868.16). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Meckel syndrome 7 (MIM# 267010), nephronophthisis 3 (MIM# 604387) and renal-hepatic-pancreatic dysplasia 1 (MIM# 208540). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR done on whole blood RNA of an affected individual demonstrated exon 20 skipping, which is expected to result in a frameshift (PMID: 30002499). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 78 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3: 1 heterozygote, 0 homozygotes). (SB) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals described to have nephronophthisis, end stage renal disease or ciliopathy syndrome and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 28921755, 30002499, 32055034). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

NPHP3-related Meckel-like syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 12, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The splice site c.2694-2_2694-1del variant has been reported to segregate with Meckel syndrome and embryonic lethality in families (Bergmann et. al., 2008). An experimental study has shown that this variant results in altered splicing, likely by usage of a cryptic splice site, resulting in a prematurely truncated protein (Fiskerstrand et. al., 2010). The c.2694-2_2694-1del variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.02759% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D, Baralle M., 2005), and loss-of-function variants in NPHP3 are known to be pathogenic (Halbritter et. al., 2013). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. The same variant (c.2694-2_2694-1del) has been observed in her father. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

Renal-hepatic-pancreatic dysplasia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous c.2694-2_2694-1del variant in NPHP3 was identified by our study in one individual with renal-hepatic-pancreatic dysplasia 1. Trio exome analysis showed this variant to be in trans with a likely pathogenic variant (ClinVar Variation ID: 635041). The c.2694-2_2694-1del variant in NPHP3 has been previously reported in 22 unrelated individuals with NPHP3-related disease (PMID: 33532864, PMID: 28973083, PMID: 32055034, PMID: 32552793, PMID: 32901917, PMID: 27894351, PMID: 33726816, PMID: 23559409, PMID: 26673778, PMID: 30002499, PMID: 33323469), but has been identified in 0.04% (14/30612) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs963574014). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 22 previously reported unrelated individuals (PMID: 33532864, PMID: 28973083, PMID: 32055034, PMID: 32552793, PMID: 32901917, PMID: 27894351, PMID: 33726816, PMID: 23559409, PMID: 26673778, PMID: 30002499, PMID: 33323469), 12 were homozygotes (PMID: 32055034, PMID: 32552793, PMID: 27894351, PMID: 18371931, PMID: 20007846) and 4 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 33532864, ClinVar Variation ID: 659899; PMID: 28973083, ClinVar Variation ID: 988261; PMID: 23559409, ClinVar Variation ID: 96511, ClinVar Variation ID: 693989 ; PMID: 30002499, ClinVar Variation ID: 262696; PMID: 33323469, ClinVar Variation ID: 1454640), which increases the likelihood that the c.2694-2_2694-1del variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 220868) and has been interpreted as pathogenic by multiple submitters. RT-PCR analysis performed on affected tissue shows evidence of altered splicing of exon 20 (PMID: 32552793, PMID: 30002499, PMID: 20007846). A different nucleotide change that also results in a splice acceptor variant at the same site, c.2694-2A>T (ClinVar Variation ID: 1524627), has been previously reported likely pathogenic, and the variant being assessed here, c.2694-2_2694-1del, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 3' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. There is an in-frame cryptic splice site 21 bases from the intron-exon boundary, providing evidence that this variant may delete 7 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Loss of function of the NPHP3 gene is an established disease mechanism in autosomal recessive renal-hepatic-pancreatic dysplasia 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive renal-hepatic-pancreatic dysplasia 1. ACMG/AMP Criteria applied: PVS1_Moderate, PS1_Supporting, PS3_Moderate, PM3_VeryStrong (Richards 2015). -

Polycystic kidney disease Pathogenic:1

Pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

-

- -

NPHP3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

The NPHP3 c.2694-2_2694-1delAG variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with NPHP3 related disorders (Bergmann et al. 2008. PubMed ID: 18371931; Meng et al 2017. PubMed ID: 28973083; Shaheen et al 2016. PubMed ID: 27894351; Shamseldin et al. 2021. PubMed ID: 34645488). Expression assays reveal that this variant leads to skipping of exon 20 (Maddirevula et al. 2020. PubMed ID: 32552793). This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 21, 2021

- -

Nephronophthisis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

This sequence change affects a splice site in intron 19 of the NPHP3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs751527253, gnomAD 0.05%). Disruption of this splice site has been observed in individual(s) with Meckel-Gruber-like syndrome and/or nephronophthisis-related ciliopathy (PMID: 18371931, 20007846, 23559409, 26673778). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 220868). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 20007846). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 21
DS_AL_spliceai		1.0		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs751527253; hg19: chr3-132408107;