1-5890953-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015102.5(NPHP4):c.2219G>A(p.Arg740His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,602,776 control chromosomes in the GnomAD database, including 782 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R740C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.022 ( 75 hom., cov: 33)

Exomes 𝑓: 0.030 ( 707 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.523

Publications

19 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006297469).

BP6

Variant 1-5890953-C-T is Benign according to our data. Variant chr1-5890953-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240967.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3388/152252) while in subpopulation NFE AF = 0.0327 (2222/68012). AF 95% confidence interval is 0.0315. There are 75 homozygotes in GnomAd4. There are 1678 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 75 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5 link	c.2219G>A	p.Arg740His	missense_variant	Exon 17 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHP4	ENST00000378156.9 link	c.2219G>A	p.Arg740His	missense_variant	Exon 17 of 30	1	NM_015102.5	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7 link	n.*1120G>A		non_coding_transcript_exon_variant	Exon 14 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.2216G>A		non_coding_transcript_exon_variant	Exon 17 of 33	2		ENSP00000423747.1	O75161-2
NPHP4	ENST00000378169.7 link	n.*1120G>A		3_prime_UTR_variant	Exon 14 of 27	1		ENSP00000367411.3	D6RA06

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3389

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00569

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.0238

Gnomad FIN

AF:

0.0323

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0247

AC:

5916

AN:

239630

AF XY:

0.0255

show subpopulations

Gnomad AFR exome

AF:

0.00500

Gnomad AMR exome

AF:

0.00994

Gnomad ASJ exome

AF:

0.0353

Gnomad EAS exome

AF:

0.000344

Gnomad FIN exome

AF:

0.0354

Gnomad NFE exome

AF:

0.0326

Gnomad OTH exome

AF:

0.0258

GnomAD4 exome

AF:

0.0300

AC:

43532

AN:

1450524

Hom.:

707

Cov.:

AF XY:

0.0300

AC XY:

21604

AN XY:

719656

show subpopulations

African (AFR)

AF:

0.00486

AC:

162

AN:

33308

American (AMR)

AF:

0.0102

AC:

451

AN:

44186

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

949

AN:

25940

East Asian (EAS)

AF:

0.000483

AC:

AN:

39316

South Asian (SAS)

AF:

0.0251

AC:

2139

AN:

85150

European-Finnish (FIN)

AF:

0.0386

AC:

2033

AN:

52708

Middle Eastern (MID)

AF:

0.0164

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0326

AC:

36045

AN:

1104302

Other (OTH)

AF:

0.0274

AC:

1640

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2281

4562

6843

9124

11405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1332

2664

3996

5328

6660

<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:

0.0223

AC:

3388

AN:

152252

Hom.:

Cov.:

AF XY:

0.0225

AC XY:

1678

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00568

AC:

236

AN:

41564

American (AMR)

AF:

0.0156

AC:

239

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

157

AN:

3472

East Asian (EAS)

AF:

0.000775

AC:

AN:

5160

South Asian (SAS)

AF:

0.0236

AC:

114

AN:

4822

European-Finnish (FIN)

AF:

0.0323

AC:

342

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0327

AC:

2222

AN:

68012

Other (OTH)

AF:

0.0217

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

162

325

487

650

812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0282

Hom.:

188

Bravo

AF:

0.0194

TwinsUK

AF:

0.0294

AC:

109

ALSPAC

AF:

0.0319

AC:

123

ESP6500AA

AF:

0.00479

AC:

ESP6500EA

AF:

0.0335

AC:

278

ExAC

AF:

0.0248

AC:

3001

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

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

- -

Apr 14, 2016

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

- -

Bardet-Biedl syndrome

Uncertain:1

Jun 02, 2023

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

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

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

- -

Atypical hemolytic-uremic syndrome

Benign:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

0.065

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.33

CADD

Benign

0.087

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.32

N;.

PhyloP100

-0.52

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.42

N;.

REVEL

Benign

0.24

Sift

Benign

0.53

T;.

Sift4G

Benign

0.37

T;T

Polyphen

0.016

B;.

Vest4

0.13

MPC

0.086

ClinPred

0.0037

GERP RS

-7.2

Varity_R

0.025

gMVP

0.28

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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