rs119456959
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_153240.5(NPHP3):c.3824_3826del(p.Gly1275del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NPHP3
NM_153240.5 inframe_deletion
NM_153240.5 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.57
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_153240.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 3-132682076-TCTC-T is Pathogenic according to our data. Variant chr3-132682076-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHP3 | NM_153240.5 | c.3824_3826del | p.Gly1275del | inframe_deletion | 27/27 | ENST00000337331.10 | |
NPHP3-ACAD11 | NR_037804.1 | n.3830_3832del | non_coding_transcript_exon_variant | 26/45 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHP3 | ENST00000337331.10 | c.3824_3826del | p.Gly1275del | inframe_deletion | 27/27 | 1 | NM_153240.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251162Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135752
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461610Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727124
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nephronophthisis Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 18, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2632). This variant is also known as delG1275. This variant has been observed in individual(s) with nephronophthisis (PMID: 12872122). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs119456959, gnomAD no frequency). This variant, c.3824_3826del, results in the deletion of 1 amino acid(s) of the NPHP3 protein (p.Gly1275del), but otherwise preserves the integrity of the reading frame. - |
Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 15, 2022 | - - |
Nephronophthisis 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2003 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at