chr1-5863996-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_015102.5(NPHP4):c.4034G>A(p.Gly1345Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPHP4 | NM_015102.5 | c.4034G>A | p.Gly1345Asp | missense_variant | Exon 29 of 30 | ENST00000378156.9 | NP_055917.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHP4 | ENST00000378156.9 | c.4034G>A | p.Gly1345Asp | missense_variant | Exon 29 of 30 | 1 | NM_015102.5 | ENSP00000367398.4 | ||
NPHP4 | ENST00000378169.7 | n.*2935G>A | non_coding_transcript_exon_variant | Exon 26 of 27 | 1 | ENSP00000367411.3 | ||||
NPHP4 | ENST00000489180.6 | n.*1845G>A | non_coding_transcript_exon_variant | Exon 32 of 33 | 2 | ENSP00000423747.1 | ||||
NPHP4 | ENST00000378169.7 | n.*2935G>A | 3_prime_UTR_variant | Exon 26 of 27 | 1 | ENSP00000367411.3 | ||||
NPHP4 | ENST00000489180.6 | n.*1845G>A | 3_prime_UTR_variant | Exon 32 of 33 | 2 | ENSP00000423747.1 |
Frequencies
GnomAD3 genomes AF: 0.000342 AC: 52AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000294 AC: 73AN: 248288Hom.: 0 AF XY: 0.000267 AC XY: 36AN XY: 134784
GnomAD4 exome AF: 0.000231 AC: 338AN: 1461494Hom.: 0 Cov.: 32 AF XY: 0.000230 AC XY: 167AN XY: 727016
GnomAD4 genome AF: 0.000342 AC: 52AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28AN XY: 74440
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Senior-Loken syndrome 4 Uncertain:1
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. -
Inborn genetic diseases Uncertain:1
The c.4034G>A (p.G1345D) alteration is located in exon 29 (coding exon 28) of the NPHP4 gene. This alteration results from a G to A substitution at nucleotide position 4034, causing the glycine (G) at amino acid position 1345 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 Uncertain:1
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Nephronophthisis Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1345 of the NPHP4 protein (p.Gly1345Asp). This variant is present in population databases (rs200407553, gnomAD 0.07%). 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: 291157). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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
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