rs201065230

Positions:

chr1-5978278-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015102.5(NPHP4):c.271T>C(p.Phe91Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00149 in 1,606,598 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 3.73

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04121715).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.271T>C	p.Phe91Leu	missense_variant	3/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.271T>C	p.Phe91Leu	missense_variant	3/30	1	NM_015102.5	P2	O75161-1

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

160

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00201

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000901

AC:

214

AN:

237496

Hom.:

AF XY:

0.000890

AC XY:

115

AN XY:

129238

show subpopulations

Gnomad AFR exome

AF:

0.000209

Gnomad AMR exome

AF:

0.0000601

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000334

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.000859

GnomAD4 exome

AF:

0.00153

AC:

2230

AN:

1454526

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1074

AN XY:

722960

show subpopulations

Gnomad4 AFR exome

AF:

0.000300

Gnomad4 AMR exome

AF:

0.0000457

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000537

Gnomad4 NFE exome

AF:

0.00193

Gnomad4 OTH exome

AF:

0.000865

GnomAD4 genome

AF:

0.00105

AC:

160

AN:

152072

Hom.:

Cov.:

AF XY:

0.000996

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00201

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.000895

ESP6500AA

AF:

0.000484

AC:

ESP6500EA

AF:

0.00167

AC:

ExAC

AF:

0.000929

AC:

112

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	Published functional studies demonstrate a damaging effect: p.F91L (described as p.F83L) failed to rescue the foraging defect and affected localization of NPHP4 in C. elegans, and was concluded to be a hypomorphic variant (Masyukova et al., 2011); Reported in published literature as heterozygous in an individual with mesocardia and laterality defects (French et al., 2012); Reported in published literature as heterozygous in a family with nephronophthisis and retinitis pigmentosa and in unrelated individuals with nephronophthisis; however, a second NPHP4 variant was not identified for these individuals (Hoefele et al., 2005; Otto et al., 2011); Identified in the heterozygous state via multi-gene panel testing in a patient with nephronophthisis who was also found to have a second heterozygous missense variant, but phase was unknown (Stokman et al., 2018); This variant is associated with the following publications: (PMID: 21546380, 22550138, 23188109, 29974258, 21068128, 15776426) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2017

The p.Phe91Leu (NM_015102.3 c.271T>C) variant in NPHP4 has been reported in 2 Ca ucasian individuals with Nephronophthisis and 1 individual with mesocardia, thou gh none with a second pathogenic variant on the other allele (Hoefele 2005, Otto 2011, and French 2012). This variant has also been reported in ClinVar (Variati on ID#16995440). This variant has been identified in 0.23% (95/41,774) of Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs201065230). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Ani mal models in C. elegans suggest that this variant is may lead to partial loss o f function; however, it is unclear how this partial loss of function may lead to disease (Masyukova 2011). In summary, the clinical significance of the p.Phe91L eu variant is uncertain. -

NPHP4-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2024

The NPHP4 c.271T>C variant is predicted to result in the amino acid substitution p.Phe91Leu. This variant has been reported in the heterozygous state in at least two different individuals with nephronophthisis; however, a second NPHP4 variant was not detected in these individuals (Hoefele et al. 2005. PubMed ID: 15776426; Otto et al. 2010. PubMed ID: 21068128). This variant was also described in a large cohort of individuals with retinal or optic nerve disorders (Dineiro et al. 2020. PubMed ID: 32483926, described as a variant of uncertain significance in Table S12) as well as in the compound heterozygous state in an individual with a suspected ciliopathy (Stokman et al. 2018. PubMed ID: 29974258, Table S1). This variant is reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Senior-Loken syndrome 4

Uncertain:1

Uncertain significance, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Senior-Loken syndrome 4;C1847013:Nephronophthisis 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Nephronophthisis 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Nephronophthisis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.041

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.2

N;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0090

D;.

Sift4G

Uncertain

0.012

D;D

Polyphen

0.18

B;.

Vest4

0.39

MutPred

0.88

Gain of catalytic residue at F91 (P = 0.0283);Gain of catalytic residue at F91 (P = 0.0283);

MVP

0.92

MPC

0.18

ClinPred

0.054

GERP RS

3.6

Varity_R

0.18

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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