1-5905321-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_015102.5(NPHP4):c.1926G>A(p.Glu642Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,612,892 control chromosomes in the GnomAD database, including 19,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1356 hom., cov: 33)

Exomes 𝑓: 0.16 ( 18497 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.740

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 1-5905321-C-T is Benign according to our data. Variant chr1-5905321-C-T is described in ClinVar as Benign. ClinVar VariationId is 95673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.74 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5 link	c.1926G>A	p.Glu642Glu	synonymous_variant	Exon 15 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHP4	ENST00000378156.9 link	c.1926G>A	p.Glu642Glu	synonymous_variant	Exon 15 of 30	1	NM_015102.5	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7 link	n.*827G>A		non_coding_transcript_exon_variant	Exon 12 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.1923G>A		non_coding_transcript_exon_variant	Exon 15 of 33	2		ENSP00000423747.1	O75161-2
NPHP4	ENST00000378169.7 link	n.*827G>A		3_prime_UTR_variant	Exon 12 of 27	1		ENSP00000367411.3	D6RA06

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17947

AN:

152132

Hom.:

1357

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0328

Gnomad AMI

AF:

0.160

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.0743

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.136

GnomAD2 exomes

AF:

0.132

AC:

32824

AN:

249286

AF XY:

0.135

show subpopulations

Gnomad AFR exome

AF:

0.0271

Gnomad AMR exome

AF:

0.0767

Gnomad ASJ exome

AF:

0.220

Gnomad EAS exome

AF:

0.0768

Gnomad FIN exome

AF:

0.136

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.155

AC:

226534

AN:

1460642

Hom.:

18497

Cov.:

AF XY:

0.155

AC XY:

112298

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.0263

AC:

881

AN:

33478

American (AMR)

AF:

0.0816

AC:

3649

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

5672

AN:

26130

East Asian (EAS)

AF:

0.0765

AC:

3035

AN:

39696

South Asian (SAS)

AF:

0.115

AC:

9899

AN:

86240

European-Finnish (FIN)

AF:

0.141

AC:

7513

AN:

53398

Middle Eastern (MID)

AF:

0.137

AC:

790

AN:

5768

European-Non Finnish (NFE)

AF:

0.167

AC:

185870

AN:

1110888

Other (OTH)

AF:

0.153

AC:

9225

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

8814

17628

26442

35256

44070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6404

12808

19212

25616

32020

<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:

0.118

AC:

17940

AN:

152250

Hom.:

1356

Cov.:

AF XY:

0.117

AC XY:

8715

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0327

AC:

1357

AN:

41554

American (AMR)

AF:

0.113

AC:

1736

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

772

AN:

3470

East Asian (EAS)

AF:

0.0741

AC:

384

AN:

5184

South Asian (SAS)

AF:

0.118

AC:

571

AN:

4822

European-Finnish (FIN)

AF:

0.131

AC:

1383

AN:

10596

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.166

AC:

11265

AN:

68008

Other (OTH)

AF:

0.135

AC:

285

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

814

1629

2443

3258

4072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.154

Hom.:

3266

Bravo

AF:

0.113

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.180

EpiControl

AF:

0.174

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 01, 2013

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

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 03, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis 4

Benign:2

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.5

(source)

DANN

Benign

0.53

PhyloP100

-0.74

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