rs571655

Positions:

chr1-5905395-C-T

Variant summary

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

The NM_015102.5(NPHP4):c.1852G>A(p.Glu618Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0118 in 1,613,372 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 7 hom., cov: 33)

Exomes 𝑓: 0.012 ( 152 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 3.89

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=0.0073396564).

BP6

Variant 1-5905395-C-T is Benign according to our data. Variant chr1-5905395-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5905395-C-T is described in Lovd as [Benign]. Variant chr1-5905395-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00997 (1518/152240) while in subpopulation NFE AF= 0.0144 (981/68012). AF 95% confidence interval is 0.0137. There are 7 homozygotes in gnomad4. There are 723 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.1852G>A	p.Glu618Lys	missense_variant	15/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.1852G>A	p.Glu618Lys	missense_variant	15/30	1	NM_015102.5	P2	O75161-1

Frequencies

GnomAD3 genomes

AF:

0.00997

AC:

1517

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.00955

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00943

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0104

AC:

2585

AN:

249266

Hom.:

AF XY:

0.0104

AC XY:

1400

AN XY:

135226

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00550

Gnomad ASJ exome

AF:

0.0311

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00294

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.0145

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0120

AC:

17540

AN:

1461132

Hom.:

152

Cov.:

AF XY:

0.0119

AC XY:

8680

AN XY:

726796

show subpopulations

Gnomad4 AFR exome

AF:

0.00370

Gnomad4 AMR exome

AF:

0.00613

Gnomad4 ASJ exome

AF:

0.0308

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00308

Gnomad4 FIN exome

AF:

0.00942

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.00997

AC:

1518

AN:

152240

Hom.:

Cov.:

AF XY:

0.00971

AC XY:

723

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00308

Gnomad4 AMR

AF:

0.00954

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00943

Gnomad4 NFE

AF:

0.0144

Gnomad4 OTH

AF:

0.00994

Alfa

AF:

0.0142

Hom.:

Bravo

AF:

0.00984

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00354

AC:

ESP6500EA

AF:

0.0148

AC:

124

ExAC

AF:

0.0103

AC:

1239

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NPHP4: BS1, BS2 -

Nephronophthisis 4

Uncertain:1Benign:1

Benign, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, no assertion criteria provided	research	Tolun Lab, Human Genetics Laboratory, Bogazici University	-	- -

not specified

Benign:2

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

Senior-Loken syndrome 4

Benign:1

Benign, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Kidney disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2019

- -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.0073

T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-2.5

N;.

REVEL

Uncertain

0.39

Sift

Uncertain

0.0050

D;.

Sift4G

Uncertain

0.019

D;D

Polyphen

1.0

D;.

Vest4

0.43

MPC

0.15

ClinPred

0.038

GERP RS

3.6

Varity_R

0.15

gMVP

0.48

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