2-110201449-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001128178.3(NPHP1):c.115C>A(p.Pro39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,608,126 control chromosomes in the GnomAD database, including 1,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. P39P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 91 hom., cov: 33)

Exomes 𝑓: 0.034 ( 1108 hom. )

Consequence

NPHP1
NM_001128178.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.109

Publications

11 publications found

Variant links:

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 Gene-Disease associations (from GenCC):

Joubert syndrome with renal defect
Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
nephronophthisis 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPHP1 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=0.0015397668).

BP6

Variant 2-110201449-G-T is Benign according to our data. Variant chr2-110201449-G-T is described in ClinVar as Benign. ClinVar VariationId is 129813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0266 (4050/152172) while in subpopulation NFE AF = 0.0395 (2685/68002). AF 95% confidence interval is 0.0382. There are 91 homozygotes in GnomAd4. There are 1965 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 91 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP1	NM_001128178.3 link	c.115C>A	p.Pro39Thr	missense_variant	Exon 2 of 20	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7 link	c.115C>A	p.Pro39Thr	missense_variant	Exon 2 of 20	1	NM_001128178.3	ENSP00000389879.3

Frequencies

GnomAD3 genomes

AF:

0.0266

AC:

4050

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.0341

Gnomad AMR

AF:

0.0254

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0513

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0394

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.0270

AC:

6715

AN:

249006

AF XY:

0.0267

show subpopulations

Gnomad AFR exome

AF:

0.00588

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0190

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0512

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0347

GnomAD4 exome

AF:

0.0340

AC:

49515

AN:

1455954

Hom.:

1108

Cov.:

AF XY:

0.0334

AC XY:

24178

AN XY:

724440

show subpopulations

African (AFR)

AF:

0.00526

AC:

176

AN:

33434

American (AMR)

AF:

0.0195

AC:

871

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

488

AN:

26034

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39636

South Asian (SAS)

AF:

0.00531

AC:

457

AN:

85998

European-Finnish (FIN)

AF:

0.0508

AC:

2674

AN:

52596

Middle Eastern (MID)

AF:

0.0387

AC:

217

AN:

5608

European-Non Finnish (NFE)

AF:

0.0387

AC:

42890

AN:

1107806

Other (OTH)

AF:

0.0289

AC:

1739

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

2090

4180

6270

8360

10450

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1556

3112

4668

6224

7780

<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:

0.0266

AC:

4050

AN:

152172

Hom.:

Cov.:

AF XY:

0.0264

AC XY:

1965

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00631

AC:

262

AN:

41548

American (AMR)

AF:

0.0254

AC:

388

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00539

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0513

AC:

542

AN:

10558

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0395

AC:

2685

AN:

68002

Other (OTH)

AF:

0.0237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

199

398

598

797

996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0340

Hom.:

253

Bravo

AF:

0.0246

TwinsUK

AF:

0.0467

AC:

173

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0388

AC:

334

ExAC

AF:

0.0267

AC:

3247

Asia WGS

AF:

0.00404

AC:

AN:

3476

EpiCase

AF:

0.0386

EpiControl

AF:

0.0385

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Feb 11, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Senior-Loken syndrome 1

Benign:1

Jan 12, 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. -

Nephronophthisis 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

- -

Joubert syndrome with renal defect

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Focal segmental glomerulosclerosis

Benign:1

Apr 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

0.073

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.072

.;.;T;.;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.68

T;T;T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;M;M;.;.

PhyloP100

-0.11

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.74

N;N;N;N;N;D

REVEL

Benign

0.059

Sift

Benign

0.089

T;T;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.0040

B;B;B;B;B;B

Vest4

0.088

MPC

0.091

ClinPred

0.010

GERP RS

0.48

PromoterAI

0.00040

Neutral

(source)

Varity_R

0.062

gMVP

0.11

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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