GeneBe

rs200407553

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 7.45
Variant links:
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPHP4NM_015102.5 linkuse as main transcriptc.4034G>A p.Gly1345Asp missense_variant 29/30 ENST00000378156.9 NP_055917.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPHP4ENST00000378156.9 linkuse as main transcriptc.4034G>A p.Gly1345Asp missense_variant 29/301 NM_015102.5 ENSP00000367398.4 O75161-1
NPHP4ENST00000378169.7 linkuse as main transcriptn.*2935G>A non_coding_transcript_exon_variant 26/271 ENSP00000367411.3 D6RA06
NPHP4ENST00000489180.6 linkuse as main transcriptn.*1845G>A non_coding_transcript_exon_variant 32/332 ENSP00000423747.1 O75161-2
NPHP4ENST00000378169.7 linkuse as main transcriptn.*2935G>A 3_prime_UTR_variant 26/271 ENSP00000367411.3 D6RA06
NPHP4ENST00000489180.6 linkuse as main transcriptn.*1845G>A 3_prime_UTR_variant 32/332 ENSP00000423747.1 O75161-2

Frequencies

GnomAD3 genomes
AF:
0.000342
AC:
52
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000382
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000294
AC:
73
AN:
248288
Hom.:
0
AF XY:
0.000267
AC XY:
36
AN XY:
134784
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000668
Gnomad ASJ exome
AF:
0.000199
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.0000934
Gnomad NFE exome
AF:
0.000364
Gnomad OTH exome
AF:
0.000497
GnomAD4 exome
AF:
0.000231
AC:
338
AN:
1461494
Hom.:
0
Cov.:
32
AF XY:
0.000230
AC XY:
167
AN XY:
727016
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000694
Gnomad4 ASJ exome
AF:
0.000153
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000231
Gnomad4 OTH exome
AF:
0.000364
GnomAD4 genome
AF:
0.000342
AC:
52
AN:
152258
Hom.:
0
Cov.:
33
AF XY:
0.000376
AC XY:
28
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000382
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000394
Hom.:
0
Bravo
AF:
0.000291
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000241
AC:
1
ESP6500EA
AF:
0.000477
AC:
4
ExAC
AF:
0.000264
AC:
32
EpiCase
AF:
0.000600
EpiControl
AF:
0.000415

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 15, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 28, 2017- -
Senior-Loken syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 16, 2021The 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
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 23, 2022- -
Nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 24, 2022This 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
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.50
D
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.71
D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Pathogenic
2.9
M
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-4.6
D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.74
MVP
0.93
MPC
0.44
ClinPred
0.55
D
GERP RS
4.2
Varity_R
0.36
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200407553; hg19: chr1-5924056; API