Genetic Variant NPHP4:p.Asp753Asn (chr1-5890915-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_015102.5(NPHP4):c.2257G>A(p.Asp753Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,610,448 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D753D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 7.39

Publications

5 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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
Senior-Loken syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
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=0.021736532).

BP6

Variant 1-5890915-C-T is Benign according to our data. Variant chr1-5890915-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194764.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00297 (453/152308) while in subpopulation AFR AF = 0.0103 (426/41558). AF 95% confidence interval is 0.00945. There are 4 homozygotes in GnomAd4. There are 218 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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	UniProt
NPHP4	NM_015102.5	MANE Select	c.2257G>A	p.Asp753Asn	missense	Exon 17 of 30	NP_055917.1	O75161-1
NPHP4	NM_001291594.2		c.721G>A	p.Asp241Asn	missense	Exon 13 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.718G>A	p.Asp240Asn	missense	Exon 14 of 27	NP_001278522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.2257G>A	p.Asp753Asn	missense	Exon 17 of 30	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7	TSL:1	n.*1158G>A		non_coding_transcript_exon	Exon 14 of 27	ENSP00000367411.3	D6RA06
NPHP4	ENST00000466897.1	TSL:1	n.334G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000425745.1	H0YA08

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

451

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

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:

0.0000735

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.000735

AC:

179

AN:

243496

AF XY:

0.000445

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000363

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000321

AC:

468

AN:

1458140

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

195

AN XY:

724942

show subpopulations

African (AFR)

AF:

0.0113

AC:

379

AN:

33422

American (AMR)

AF:

0.000450

AC:

AN:

44440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52902

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1110088

Other (OTH)

AF:

0.000498

AC:

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00297

AC:

453

AN:

152308

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

218

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0103

AC:

426

AN:

41558

American (AMR)

AF:

0.000914

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68030

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000912

Hom.:

Bravo

AF:

0.00325

ESP6500AA

AF:

0.00812

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000794

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Nephronophthisis 4 (2)

Kidney disorder (1)

Nephronophthisis (1)

Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.022

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.8

PhyloP100

7.4

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.94

MVP

0.97

MPC

0.39

ClinPred

0.038

GERP RS

5.6

Varity_R

0.72

gMVP

0.79

Mutation Taster

=82/18

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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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

Computational scores

Splicing

Publications

Other links and lift over