rs201433248
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_015102.5(NPHP4):c.3052G>A(p.Val1018Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,611,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_015102.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHP4 | NM_015102.5 | c.3052G>A | p.Val1018Met | missense_variant | 22/30 | ENST00000378156.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHP4 | ENST00000378156.9 | c.3052G>A | p.Val1018Met | missense_variant | 22/30 | 1 | NM_015102.5 | P2 | |
NPHP4 | ENST00000378169.7 | c.*1953G>A | 3_prime_UTR_variant, NMD_transcript_variant | 19/27 | 1 | ||||
NPHP4 | ENST00000478423.6 | n.2784G>A | non_coding_transcript_exon_variant | 18/26 | 2 | ||||
NPHP4 | ENST00000489180.6 | c.*863G>A | 3_prime_UTR_variant, NMD_transcript_variant | 25/33 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000114 AC: 28AN: 245268Hom.: 0 AF XY: 0.000135 AC XY: 18AN XY: 133304
GnomAD4 exome AF: 0.000119 AC: 173AN: 1459234Hom.: 0 Cov.: 34 AF XY: 0.000110 AC XY: 80AN XY: 725788
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74350
ClinVar
Submissions by phenotype
Senior-Loken syndrome 4 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. - |
Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 27, 2022 | - - |
Nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1018 of the NPHP4 protein (p.Val1018Met). This variant is present in population databases (rs201433248, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NPHP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 220869). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHP4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Nephronophthisis 4 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at