rs12142270

Positions:

chr1-5986204-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015102.5(NPHP4):c.86C>T(p.Thr29Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,613,662 control chromosomes in the GnomAD database, including 922 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. T29T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.042 ( 187 hom., cov: 33)

Exomes 𝑓: 0.027 ( 735 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.911

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=0.0019364357).

BP6

Variant 1-5986204-G-A is Benign according to our data. Variant chr1-5986204-G-A is described in ClinVar as [Benign]. Clinvar id is 260561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5986204-G-A is described in Lovd as [Benign]. Variant chr1-5986204-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.86C>T	p.Thr29Met	missense_variant	2/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.86C>T	p.Thr29Met	missense_variant	2/30	1	NM_015102.5	P2	O75161-1

Frequencies

GnomAD3 genomes

AF:

0.0419

AC:

6374

AN:

152154

Hom.:

188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0866

Gnomad AMI

AF:

0.0670

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0248

Gnomad OTH

AF:

0.0441

GnomAD3 exomes

AF:

0.0291

AC:

7253

AN:

248848

Hom.:

179

AF XY:

0.0286

AC XY:

3864

AN XY:

135072

show subpopulations

Gnomad AFR exome

AF:

0.0877

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0318

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0320

Gnomad FIN exome

AF:

0.0449

Gnomad NFE exome

AF:

0.0274

Gnomad OTH exome

AF:

0.0308

GnomAD4 exome

AF:

0.0272

AC:

39757

AN:

1461390

Hom.:

735

Cov.:

AF XY:

0.0270

AC XY:

19635

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.0913

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0333

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0332

Gnomad4 FIN exome

AF:

0.0445

Gnomad4 NFE exome

AF:

0.0253

Gnomad4 OTH exome

AF:

0.0292

GnomAD4 genome

AF:

0.0419

AC:

6374

AN:

152272

Hom.:

187

Cov.:

AF XY:

0.0415

AC XY:

3089

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0863

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0268

Gnomad4 FIN

AF:

0.0432

Gnomad4 NFE

AF:

0.0248

Gnomad4 OTH

AF:

0.0436

Alfa

AF:

0.0281

Hom.:

159

Bravo

AF:

0.0419

TwinsUK

AF:

0.0299

AC:

111

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.0781

AC:

320

ESP6500EA

AF:

0.0251

AC:

210

ExAC

AF:

0.0320

AC:

3874

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0233

EpiControl

AF:

0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	GeneDx	May 04, 2021	- -

Nephronophthisis 4

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2018

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.69

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.81

N;.

REVEL

Benign

0.25

Sift

Uncertain

0.010

D;.

Sift4G

Uncertain

0.027

D;D

Polyphen

0.99

D;.

Vest4

0.21

MPC

0.081

ClinPred

0.011

GERP RS

3.8

Varity_R

0.050

gMVP

0.34

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