2-110163048-C-T

Position:

chr2-110163048-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001128178.3(NPHP1):c.859G>A(p.Gly287Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000187 in 1,610,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

NPHP1
NM_001128178.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.25

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-110163048-C-T is Pathogenic according to our data. Variant chr2-110163048-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-110163048-C-T is described in Lovd as [Pathogenic]. Variant chr2-110163048-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP1	NM_001128178.3 linkuse as main transcript	c.859G>A	p.Gly287Arg	missense_variant, splice_region_variant	9/20	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7 linkuse as main transcript	c.859G>A	p.Gly287Arg	missense_variant, splice_region_variant	9/20	1	NM_001128178.3	ENSP00000389879	P2	O15259-2

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

251006

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

283

AN:

1458296

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

725760

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000246

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000118

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2021	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; Published functional studies in an individual who was compound heterozygous for the c.1027 G>A variant and a NPHP1 deletion demonstrated multiple splice products of aberrant size and no correctly spliced product (Otto et al., 2008); This variant is associated with the following publications: (PMID: 26582918, 27535533, 30773290, 18076122, 24154662, 23559409, 17409309, 10839884, 16762963, 19165332, 25525159, 28559085, 29974258) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Nephronophthisis 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Feb 14, 2019	- -

NPHP1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 03, 2018

The NPHP1 c.1027G>A (p.Gly343Arg) variant, also known as p.Gly342Arg, has been reported in four studies and in a total of nine probands including one in a homozygous state, and at least seven probands in a compound heterozygous state (Betz et al. 2000; Hildebrandt et al. 2001; Otto et al. 2008; Wang et al. 2014; Stokman et al. 2018). In one additional proband, the parental DNA was not available so phase is not known but the proband is indicated to either be compound heterozygous or homozygous for p.Gly343Arg. The variant The p.Gly343Arg variant was absent from 70 control subjects and is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. Otto et al. (2008) demonstrated aberrant splicing in total RNA extracted from lymphocytes from an affected individual who was compound heterozygous for this variant. Based on the evidence, the p.Gly343Arg is classified as pathogenic for NPHP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2021

The c.1027G>A (p.G343R) alteration is located in exon 9 (coding exon 9) of the NPHP1 gene. This alteration results from a G to A substitution at nucleotide position 1027, causing the glycine (G) at amino acid position 343 to be replaced by an arginine (R). However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. Based on data from the Genome Aggregation Database (gnomAD) database, the NPHP1 c.1027G>A alteration was observed in 0.01% (31/282388) of total alleles studied, with a frequency of 0.02% (26/128868) in the European (non-Finnish) subpopulation. This alteration has been identified in the homozygous state and compound heterozygous with NPHP1 whole-gene deletion in multiple patients with NPHP1-related ciliopathies (Tory, 2007; Otto, 2008; Halbritter, 2013; Schueler, 2016; Connaughton, 2019). This nucleotide position is highly conserved in available vertebrate species. Functional RNA studies in an affected patient demonstrated aberrant splicing (Otto, 2008). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, the in silico protein prediction for the p.G343R alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Nephronophthisis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 343 of the NPHP1 protein (p.Gly343Arg). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121907899, gnomAD 0.02%). This missense change has been observed in individual(s) with nephronophthisis (PMID: 10839884, 11168925, 16762963, 18076122, 23559409, 24154662, 26673778). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3510). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Joubert syndrome with renal defect

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

.;.;T;.;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Uncertain

-0.0026

MutationAssessor

Benign

1.9

.;.;L;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.57

MutPred

0.68

.;.;Gain of solvent accessibility (P = 0.0584);.;.;

MVP

0.95

MPC

0.48

ClinPred

0.30

GERP RS

5.8

Varity_R

0.47

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.70

Position offset: 0

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