rs751527253

Variant names:

• chr3-132689263-CCT-C
• rs751527253
• NM_153240.5:c.2694-2_2694-1delAG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV004047650: 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)." and additional evidence is available in ClinVar.

• 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:28
• Conservation: PhyloP100: 7.47
• Publications: 9 publications found

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]

ACMG classification

Our verdict: Pathogenic. The variant received 20 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004047650: 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).; SCV000693903: RT-PCR analysis performed on affected tissue shows evidence of altered splicing of exon 20 (PMID: 32552793, PMID: 30002499, PMID: 20007846).; SCV000261757: Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20007846).; SCV000329431: Published functional studies demonstrate this variant leads to loss of splice acceptor resulting in skipping of exon 20 (Molinari et al., 2018); SCV002766885: 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).; SCV004115080: Expression assays reveal that this variant leads to skipping of exon 20 (Maddirevula et al. 2020. PubMed ID: 32552793).
• PP5: Variant 3-132689263-CCT-C is Pathogenic according to our data. Variant chr3-132689263-CCT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 220868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153240.5. 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
	NPHP3	NM_153240.5	MANE Select	c.2694-2_2694-1delAG		splice_acceptor intron	N/A	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.2700-2_2700-1delAG		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.2694-2_2694-1delAG		splice_acceptor intron	N/A	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000971413.1		c.2493-2_2493-1delAG		splice_acceptor intron	N/A	ENSP00000641472.1
	NPHP3	ENST00000971412.1		c.2271-2_2271-1delAG		splice_acceptor intron	N/A	ENSP00000641471.1

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

GnomAD2 exomes AF: 0.000275 AC: 69 AN: 251300 AF XY: 0.000309

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 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

African (AFR) AF: 0.000209 AC: 7 AN: 33476

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86250

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000246 AC: 274 AN: 1111852

Other (OTH) AF: 0.000149 AC: 9 AN: 60394

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

African (AFR) AF: 0.000313 AC: 13 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
5	-	-	Nephronophthisis 3 (5)
3	-	-	NPHP3-related disorder (3)
3	-	-	NPHP3-related Meckel-like syndrome (3)
2	-	-	Nephronophthisis (2)
2	-	-	Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 (2)
2	-	-	Renal-hepatic-pancreatic dysplasia 1 (2)
1	-	-	Joubert syndrome and related disorders (1)
1	-	-	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs751527253; hg19: chr3-132408107;