Variant summary

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

The NM_015102.5(NPHP4):c.1024C>T(p.Arg342Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,796 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts 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. R342H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 10 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 2.98

Publications

8 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=0.013156593).

BP6

Variant 1-5947199-G-A is Benign according to our data. Variant chr1-5947199-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281181.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00135 (205/152208) while in subpopulation AMR AF = 0.00588 (90/15298). AF 95% confidence interval is 0.0049. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015102.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP4	NM_015102.5	MANE Select	c.1024C>T	p.Arg342Cys	missense	Exon 9 of 30	NP_055917.1
NPHP4	NM_001291594.2		c.-343C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.-343C>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 27	NP_001278522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.1024C>T	p.Arg342Cys	missense	Exon 9 of 30	ENSP00000367398.4
NPHP4	ENST00000378169.7	TSL:1	n.*98C>T		non_coding_transcript_exon	Exon 8 of 27	ENSP00000367411.3
NPHP4	ENST00000489180.6	TSL:2	n.1024C>T		non_coding_transcript_exon	Exon 9 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00164

AC:

409

AN:

249242

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00115

AC:

1685

AN:

1461588

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1001

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33478

American (AMR)

AF:

0.00203

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.00583

AC:

503

AN:

86248

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000755

AC:

839

AN:

1111802

Other (OTH)

AF:

0.00184

AC:

111

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

171

256

342

427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00135

AC:

205

AN:

152208

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41510

American (AMR)

AF:

0.00588

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00518

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

68024

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00115

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.00138

AC:

167

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Kidney disorder (1)

Nephronophthisis (1)

Nephronophthisis 4 (1)

not provided (1)

not specified (1)

Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.4

PhyloP100

3.0

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.43

MVP

0.98

MPC

0.10

ClinPred

0.059

GERP RS

5.3

Varity_R

0.20

gMVP

0.52

Mutation Taster

=89/11

polymorphism

(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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rs190940697

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over