rs369950850

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015102.5(NPHP4):c.3161G>A(p.Arg1054His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,599,360 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1054C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.29

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
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

new If you want to explore the variant's impact on the transcript NM_015102.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38387805).

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.3161G>A	p.Arg1054His	missense	Exon 22 of 30	NP_055917.1	O75161-1
NPHP4	NM_001291594.2		c.1625G>A	p.Arg542His	missense	Exon 18 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.1622G>A	p.Arg541His	missense	Exon 19 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.3161G>A	p.Arg1054His	missense	Exon 22 of 30	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7	TSL:1	n.*2062G>A		non_coding_transcript_exon	Exon 19 of 27	ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6	TSL:2	n.*972G>A		non_coding_transcript_exon	Exon 25 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000262

AC:

AN:

225484

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.000787

Gnomad AMR exome

AF:

0.000558

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000482

Gnomad FIN exome

AF:

0.000512

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

180

AN:

1447108

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

718244

show subpopulations

African (AFR)

AF:

0.000483

AC:

AN:

33094

American (AMR)

AF:

0.000443

AC:

AN:

42890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25652

East Asian (EAS)

AF:

0.000384

AC:

AN:

39038

South Asian (SAS)

AF:

0.000252

AC:

AN:

83428

European-Finnish (FIN)

AF:

0.000502

AC:

AN:

51824

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000669

AC:

AN:

1105660

Other (OTH)

AF:

0.000134

AC:

AN:

59790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000342

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41550

American (AMR)

AF:

0.000262

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.000184

Hom.:

Bravo

AF:

0.000310

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Nephronophthisis (1)

not provided (1)

NPHP4-related disorder (1)

Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.1

PhyloP100

7.3

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.72

Mutation Taster

=51/49

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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