1-5874521-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_015102.5(NPHP4):c.3181G>A(p.Val1061Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,585,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. V1061F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: -0.126

Publications

0 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012656927).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000519 (79/152250) while in subpopulation AFR AF = 0.00161 (67/41548). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3181G>A	p.Val1061Ile	missense	Exon 22 of 30	NP_055917.1	O75161-1
NPHP4	NM_001291594.2		c.1645G>A	p.Val549Ile	missense	Exon 18 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.1642G>A	p.Val548Ile	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.3181G>A	p.Val1061Ile	missense	Exon 22 of 30	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7	TSL:1	n.*2082G>A		non_coding_transcript_exon	Exon 19 of 27	ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6	TSL:2	n.*992G>A		non_coding_transcript_exon	Exon 25 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000140

AC:

AN:

207022

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.000611

Gnomad AMR exome

AF:

0.0000664

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000667

Gnomad FIN exome

AF:

0.0000543

Gnomad NFE exome

AF:

0.000109

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.000148

AC:

212

AN:

1433332

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

709958

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

32802

American (AMR)

AF:

0.0000733

AC:

AN:

40938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25444

East Asian (EAS)

AF:

0.0000784

AC:

AN:

38250

South Asian (SAS)

AF:

0.000171

AC:

AN:

82058

European-Finnish (FIN)

AF:

0.0000392

AC:

AN:

51012

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000100

AC:

110

AN:

1097874

Other (OTH)

AF:

0.000304

AC:

AN:

59240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000519

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41548

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000337

Hom.:

Bravo

AF:

0.000499

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000944

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000191

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Nephronophthisis (1)

Nephronophthisis 4 (1)

not specified (1)

Senior-Loken syndrome 4 (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

CADD

Benign

0.077

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.088

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.60

M_CAP

Benign

0.014

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.71

PhyloP100

-0.13

PrimateAI

Benign

0.28

PROVEAN

Benign

0.19

REVEL

Uncertain

0.40

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.14

MVP

0.37

MPC

0.054

ClinPred

0.0040

GERP RS

-5.5

Varity_R

0.012

gMVP

0.23

Mutation Taster

=39/61

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over