rs571655
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_015102.5(NPHP4):c.1852G>A(p.Glu618Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0118 in 1,613,372 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.010 ( 7 hom., cov: 33)
Exomes 𝑓: 0.012 ( 152 hom. )
Consequence
NPHP4
NM_015102.5 missense
NM_015102.5 missense
Scores
10
8
Clinical Significance
Conservation
PhyloP100: 3.89
Genes affected
NPHP4 (HGNC:19104): (nephrocystin 4) This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0073396564).
BP6
Variant 1-5905395-C-T is Benign according to our data. Variant chr1-5905395-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5905395-C-T is described in Lovd as [Benign]. Variant chr1-5905395-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00997 (1518/152240) while in subpopulation NFE AF= 0.0144 (981/68012). AF 95% confidence interval is 0.0137. There are 7 homozygotes in gnomad4. There are 723 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPHP4 | NM_015102.5 | c.1852G>A | p.Glu618Lys | missense_variant | 15/30 | ENST00000378156.9 | NP_055917.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHP4 | ENST00000378156.9 | c.1852G>A | p.Glu618Lys | missense_variant | 15/30 | 1 | NM_015102.5 | ENSP00000367398.4 | ||
NPHP4 | ENST00000378169.7 | n.*753G>A | non_coding_transcript_exon_variant | 12/27 | 1 | ENSP00000367411.3 | ||||
NPHP4 | ENST00000489180.6 | n.1849G>A | non_coding_transcript_exon_variant | 15/33 | 2 | ENSP00000423747.1 | ||||
NPHP4 | ENST00000378169.7 | n.*753G>A | 3_prime_UTR_variant | 12/27 | 1 | ENSP00000367411.3 |
Frequencies
GnomAD3 genomes AF: 0.00997 AC: 1517AN: 152122Hom.: 7 Cov.: 33
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GnomAD3 exomes AF: 0.0104 AC: 2585AN: 249266Hom.: 20 AF XY: 0.0104 AC XY: 1400AN XY: 135226
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GnomAD4 exome AF: 0.0120 AC: 17540AN: 1461132Hom.: 152 Cov.: 32 AF XY: 0.0119 AC XY: 8680AN XY: 726796
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GnomAD4 genome AF: 0.00997 AC: 1518AN: 152240Hom.: 7 Cov.: 33 AF XY: 0.00971 AC XY: 723AN XY: 74444
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | NPHP4: BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Nephronophthisis 4 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Uncertain significance, no assertion criteria provided | research | Tolun Lab, Human Genetics Laboratory, Bogazici University | - | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Senior-Loken syndrome 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Kidney disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 01, 2019 | - - |
Nephronophthisis Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at