rs116174472
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The NM_153240.5(NPHP3):c.2769C>T(p.Phe923=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,614,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00085 ( 3 hom. )
Consequence
NPHP3
NM_153240.5 synonymous
NM_153240.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.78
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 Benign. Variant got -12 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.45).
BP6
Variant 3-132689188-G-A is Benign according to our data. Variant chr3-132689188-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289555.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=1}. Variant chr3-132689188-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.78 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000631 (96/152230) while in subpopulation NFE AF= 0.00109 (74/68024). AF 95% confidence interval is 0.000888. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| NPHP3 | NM_153240.5 | c.2769C>T | p.Phe923= | synonymous_variant | 20/27 | ENST00000337331.10 | |
| NPHP3-ACAD11 | NR_037804.1 | n.2775C>T | non_coding_transcript_exon_variant | 19/45 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NPHP3 | ENST00000337331.10 | c.2769C>T | p.Phe923= | synonymous_variant | 20/27 | 1 | NM_153240.5 | P1 |
Frequencies
GnomAD3 genomes 0.000631 AC: 96AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000815 AC: 205AN: 251406Hom.: 0 AF XY: 0.000736 AC XY: 100AN XY: 135872
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GnomAD4 exome AF: 0.000854 AC: 1248AN: 1461820Hom.: 3 Cov.: 32 AF XY: 0.000843 AC XY: 613AN XY: 727214
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GnomAD4 genome 0.000631 AC: 96AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | NPHP3: BP4, BP7 - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2020 | - - |
not specified Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 15, 2016 | - - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Renal-hepatic-pancreatic dysplasia 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
NPHP3-related Meckel-like syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Nephronophthisis 3 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Nephronophthisis Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at