rs17472401

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015102.5(NPHP4):c.2542C>T(p.Arg848Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,613,640 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R848Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 25 hom., cov: 33)

Exomes 𝑓: 0.022 ( 410 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 1.48

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]

NPHP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007936746).

BP6

Variant 1-5880183-G-A is Benign according to our data. Variant chr1-5880183-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5880183-G-A is described in Lovd as [Benign]. Variant chr1-5880183-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0156 (2378/152308) while in subpopulation NFE AF= 0.0237 (1614/68022). AF 95% confidence interval is 0.0228. There are 25 homozygotes in gnomad4. There are 1132 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5 link	c.2542C>T	p.Arg848Trp	missense_variant	Exon 19 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHP4	ENST00000378156.9 link	c.2542C>T	p.Arg848Trp	missense_variant	Exon 19 of 30	1	NM_015102.5	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7 link	n.*1443C>T		non_coding_transcript_exon_variant	Exon 16 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.2539C>T		non_coding_transcript_exon_variant	Exon 19 of 33	2		ENSP00000423747.1	O75161-2
NPHP4	ENST00000378169.7 link	n.*1443C>T		3_prime_UTR_variant	Exon 16 of 27	1		ENSP00000367411.3	D6RA06

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2378

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.00811

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.0259

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0155

AC:

3841

AN:

248334

Hom.:

AF XY:

0.0157

AC XY:

2120

AN XY:

134758

show subpopulations

Gnomad AFR exome

AF:

0.00358

Gnomad AMR exome

AF:

0.00418

Gnomad ASJ exome

AF:

0.0288

Gnomad EAS exome

AF:

0.000502

Gnomad SAS exome

AF:

0.00469

Gnomad FIN exome

AF:

0.0252

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0216

AC:

31535

AN:

1461332

Hom.:

410

Cov.:

AF XY:

0.0213

AC XY:

15449

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00358

Gnomad4 AMR exome

AF:

0.00466

Gnomad4 ASJ exome

AF:

0.0282

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00505

Gnomad4 FIN exome

AF:

0.0248

Gnomad4 NFE exome

AF:

0.0247

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0156

AC:

2378

AN:

152308

Hom.:

Cov.:

AF XY:

0.0152

AC XY:

1132

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00435

Gnomad4 AMR

AF:

0.00803

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00455

Gnomad4 FIN

AF:

0.0259

Gnomad4 NFE

AF:

0.0237

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0209

Hom.:

Bravo

AF:

0.0140

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0219

AC:

184

ExAC

AF:

0.0147

AC:

1785

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0230

EpiControl

AF:

0.0215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nephronophthisis 4

Pathogenic:1Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Arg848Trp variant in NPHP4 has been identified in 3 individuals with nephronophthisis, segregated with disease in 3 relatives from 1 family (PMID: 12205563), but has also been identified in >2% of European (Finnish) chromosomes and 15 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive nephronophthisis. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Nov 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 22, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHP4: BS1, BS2 -

Kidney disorder

Benign:1

Feb 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

0.030

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0079

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.0

D;.

REVEL

Uncertain

0.48

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;.

Vest4

0.58

MPC

0.40

ClinPred

0.015

GERP RS

0.78

Varity_R

0.11

gMVP

0.47

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over