rs113445782

Variant summary

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

The NM_015102.5(NPHP4):c.3479C>T(p.Pro1160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,610,202 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1160P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 21 hom., cov: 33)

Exomes 𝑓: 0.014 ( 185 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.22

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=0.010002285).

BP6

Variant 1-5867109-G-A is Benign according to our data. Variant chr1-5867109-G-A is described in ClinVar as [Benign]. Clinvar id is 220304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5867109-G-A is described in Lovd as [Benign]. Variant chr1-5867109-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0112 (1706/152224) while in subpopulation AMR AF= 0.0188 (288/15302). AF 95% confidence interval is 0.017. There are 21 homozygotes in gnomad4. There are 766 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.3479C>T	p.Pro1160Leu	missense_variant	25/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.3479C>T	p.Pro1160Leu	missense_variant	25/30	1	NM_015102.5	P2	O75161-1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1707

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00372

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0164

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0111

AC:

2684

AN:

242320

Hom.:

AF XY:

0.0116

AC XY:

1524

AN XY:

131374

show subpopulations

Gnomad AFR exome

AF:

0.00291

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0214

Gnomad EAS exome

AF:

0.000682

Gnomad SAS exome

AF:

0.00507

Gnomad FIN exome

AF:

0.00338

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.0143

AC:

20897

AN:

1457978

Hom.:

185

Cov.:

AF XY:

0.0141

AC XY:

10255

AN XY:

724950

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.0142

Gnomad4 ASJ exome

AF:

0.0221

Gnomad4 EAS exome

AF:

0.000556

Gnomad4 SAS exome

AF:

0.00490

Gnomad4 FIN exome

AF:

0.00416

Gnomad4 NFE exome

AF:

0.0163

Gnomad4 OTH exome

AF:

0.0140

GnomAD4 genome

AF:

0.0112

AC:

1706

AN:

152224

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

766

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.00371

Gnomad4 AMR

AF:

0.0188

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00437

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.0164

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0129

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.0180

AC:

150

ExAC

AF:

0.0103

AC:

1250

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NPHP4: BP4, BS1, BS2 -

Senior-Loken syndrome 4

Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2018

- -

Nephronophthisis 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Benign

0.76

DEOGEN2

Benign

0.36

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.72

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.56

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.20

Sift

Benign

0.10

Sift4G

Benign

0.10

Polyphen

0.56

Vest4

0.32

MPC

0.071

ClinPred

0.024

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.063

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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