rs33958626

chr2-110201449-G-T

Variant summary

Our verdict is Benign. Variant got -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. 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. 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:12

Conservation

PhyloP100: -0.109

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 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=0.0015397668).

BP6

Variant 2-110201449-G-T is Benign according to our data. Variant chr2-110201449-G-T is described in ClinVar as [Benign]. Clinvar id is 129813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-110201449-G-T is described in Lovd as [Benign]. Variant chr2-110201449-G-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 91 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP1	NM_001128178.3 linkuse as main transcript	c.115C>A	p.Pro39Thr	missense_variant	2/20	ENST00000445609.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP1	ENST00000445609.7 linkuse as main transcript	c.115C>A	p.Pro39Thr	missense_variant	2/20	1	NM_001128178.3	P2	O15259-2

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

GnomAD3 exomes

AF:

0.0270

AC:

6715

AN:

249006

Hom.:

152

AF XY:

0.0267

AC XY:

3590

AN XY:

134580

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 SAS exome

AF:

0.00477

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

Gnomad4 AFR exome

AF:

0.00526

Gnomad4 AMR exome

AF:

0.0195

Gnomad4 ASJ exome

AF:

0.0187

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00531

Gnomad4 FIN exome

AF:

0.0508

Gnomad4 NFE exome

AF:

0.0387

Gnomad4 OTH exome

AF:

0.0289

GnomAD4 genome

AF:

0.0266

AC:

4050

AN:

152172

Hom.:

Cov.:

AF XY:

0.0264

AC XY:

1965

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00631

Gnomad4 AMR

AF:

0.0254

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0513

Gnomad4 NFE

AF:

0.0395

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0327

Hom.:

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2016	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. -

Senior-Loken syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Joubert syndrome with renal defect

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

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

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2020

- -

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

Dann

Benign

0.83

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;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

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

Varity_R

0.062

gMVP

0.11

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

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