rs12142270

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
Senior-Loken syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
nephronophthisis 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPHP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 260561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NPHP4	NM_015102.5 link	c.86C>T	p.Thr29Met	missense_variant	Exon 2 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHP4	ENST00000378156.9 link	c.86C>T	p.Thr29Met	missense_variant	Exon 2 of 30	1	NM_015102.5	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7 link	n.86C>T		non_coding_transcript_exon_variant	Exon 2 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.86C>T		non_coding_transcript_exon_variant	Exon 2 of 33	2		ENSP00000423747.1	O75161-2

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

GnomAD2 exomes

AF:

0.0291

AC:

7253

AN:

248848

AF XY:

0.0286

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 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

African (AFR)

AF:

0.0913

AC:

3054

AN:

33468

American (AMR)

AF:

0.0119

AC:

532

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0333

AC:

869

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0332

AC:

2861

AN:

86212

European-Finnish (FIN)

AF:

0.0445

AC:

2374

AN:

53366

Middle Eastern (MID)

AF:

0.0352

AC:

203

AN:

5766

European-Non Finnish (NFE)

AF:

0.0253

AC:

28099

AN:

1111674

Other (OTH)

AF:

0.0292

AC:

1762

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1983

3967

5950

7934

9917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1110

2220

3330

4440

5550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0419

AC:

6374

AN:

152272

Hom.:

187

Cov.:

AF XY:

0.0415

AC XY:

3089

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0863

AC:

3587

AN:

41542

American (AMR)

AF:

0.0158

AC:

242

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5194

South Asian (SAS)

AF:

0.0268

AC:

129

AN:

4822

European-Finnish (FIN)

AF:

0.0432

AC:

458

AN:

10608

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0248

AC:

1688

AN:

68016

Other (OTH)

AF:

0.0436

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

337

674

1010

1347

1684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0292

Hom.:

371

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis 4

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Senior-Loken syndrome 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Kidney disorder

Benign:1

Jul 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

0.91

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over