rs199875059

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_015102.5(NPHP4):c.2557G>T(p.Asp853Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,613,514 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00059 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 8 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.44

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008684099).

BP6

Variant 1-5880168-C-A is Benign according to our data. Variant chr1-5880168-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297804.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.2557G>T	p.Asp853Tyr	missense_variant	19/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.2557G>T	p.Asp853Tyr	missense_variant	19/30	1	NM_015102.5	P2	O75161-1

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00111

AC:

276

AN:

248156

Hom.:

AF XY:

0.00108

AC XY:

146

AN XY:

134680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.0234

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000240

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.000578

AC:

845

AN:

1461352

Hom.:

Cov.:

AF XY:

0.000587

AC XY:

427

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0239

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.000591

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0205

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.000661

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00155

AC:

ExAC

AF:

0.000818

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Senior-Loken syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Nephronophthisis 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 19, 2017

- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.0087

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.1

D;.

REVEL

Benign

0.22

Sift

Uncertain

0.0080

D;.

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.85

P;.

Vest4

0.52

MVP

0.87

MPC

0.41

ClinPred

0.13

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.46

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