1-5947199-G-A

Position:

chr1-5947199-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000378156.9(NPHP4):c.1024C>T(p.Arg342Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,796 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R342H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 10 hom. )

Consequence

NPHP4
ENST00000378156.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.98

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013156593).

BP6

Variant 1-5947199-G-A is Benign according to our data. Variant chr1-5947199-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281181.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=3}. Variant chr1-5947199-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00135 (205/152208) while in subpopulation AMR AF= 0.00588 (90/15298). AF 95% confidence interval is 0.0049. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.1024C>T	p.Arg342Cys	missense_variant	9/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.1024C>T	p.Arg342Cys	missense_variant	9/30	1	NM_015102.5	ENSP00000367398	P2	O75161-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00164

AC:

409

AN:

249242

Hom.:

AF XY:

0.00197

AC XY:

266

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00542

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00115

AC:

1685

AN:

1461588

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1001

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00149

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00583

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000755

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152208

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00588

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.00138

AC:

167

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Kidney disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 16, 2017

- -

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. -

Nephronophthisis 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 29, 2016

- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

NPHP4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.1

D;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.43

MVP

0.98

MPC

0.10

ClinPred

0.059

GERP RS

5.3

Varity_R

0.20

gMVP

0.52

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