2-110165126-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001128178.3(NPHP1):c.654G>A(p.Glu218Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,610,892 control chromosomes in the GnomAD database, including 104,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12033 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92455 hom. )

Consequence

NPHP1
NM_001128178.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.68

Publications

27 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 2-110165126-C-T is Benign according to our data. Variant chr2-110165126-C-T is described in ClinVar as Benign. ClinVar VariationId is 92719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.68 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP1	NM_001128178.3 link	c.654G>A	p.Glu218Glu	synonymous_variant	Exon 7 of 20	ENST00000445609.7	NP_001121650.1	O15259-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7 link	c.654G>A	p.Glu218Glu	synonymous_variant	Exon 7 of 20	1	NM_001128178.3	ENSP00000389879.3		O15259-2

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58504

AN:

151846

Hom.:

11998

Cov.:

show subpopulations

Gnomad AFR

AF:

0.489

Gnomad AMI

AF:

0.347

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.332

Gnomad EAS

AF:

0.575

Gnomad SAS

AF:

0.498

Gnomad FIN

AF:

0.225

Gnomad MID

AF:

0.404

Gnomad NFE

AF:

0.323

Gnomad OTH

AF:

0.381

GnomAD2 exomes

AF:

0.375

AC:

94183

AN:

251334

AF XY:

0.378

show subpopulations

Gnomad AFR exome

AF:

0.493

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.329

Gnomad EAS exome

AF:

0.594

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.352

GnomAD4 exome

AF:

0.347

AC:

506143

AN:

1458928

Hom.:

92455

Cov.:

AF XY:

0.351

AC XY:

254713

AN XY:

725924

show subpopulations

African (AFR)

AF:

0.495

AC:

16516

AN:

33366

American (AMR)

AF:

0.365

AC:

16318

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

8639

AN:

26106

East Asian (EAS)

AF:

0.590

AC:

23392

AN:

39638

South Asian (SAS)

AF:

0.498

AC:

42865

AN:

86160

European-Finnish (FIN)

AF:

0.230

AC:

12276

AN:

53386

Middle Eastern (MID)

AF:

0.393

AC:

2263

AN:

5760

European-Non Finnish (NFE)

AF:

0.326

AC:

362138

AN:

1109534

Other (OTH)

AF:

0.361

AC:

21736

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

15085

30169

45254

60338

75423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12044

24088

36132

48176

60220

<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:

0.386

AC:

58601

AN:

151964

Hom.:

12033

Cov.:

AF XY:

0.387

AC XY:

28759

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.490

AC:

20289

AN:

41426

American (AMR)

AF:

0.406

AC:

6193

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

1152

AN:

3468

East Asian (EAS)

AF:

0.575

AC:

2966

AN:

5156

South Asian (SAS)

AF:

0.499

AC:

2404

AN:

4814

European-Finnish (FIN)

AF:

0.225

AC:

2378

AN:

10556

Middle Eastern (MID)

AF:

0.411

AC:

120

AN:

292

European-Non Finnish (NFE)

AF:

0.323

AC:

21983

AN:

67970

Other (OTH)

AF:

0.380

AC:

801

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1747

3493

5240

6986

8733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<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:

0.351

Hom.:

29590

Bravo

AF:

0.399

Asia WGS

AF:

0.516

AC:

1791

AN:

3478

EpiCase

AF:

0.337

EpiControl

AF:

0.336

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 23, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 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. -

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. -

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

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

- -

Senior-Loken syndrome 1

Benign:2

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis 1

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joubert syndrome with renal defect

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.31

(source)

DANN

Benign

0.36

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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