1-5873275-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_015102.5(NPHP4):c.3292G>A(p.Ala1098Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,613,888 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1098S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -1.15

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05028823).

BP6

Variant 1-5873275-C-T is Benign according to our data. Variant chr1-5873275-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 500975.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000722 (110/152302) while in subpopulation NFE AF = 0.00137 (93/68004). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5 link	c.3292G>A	p.Ala1098Thr	missense_variant	Exon 23 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHP4	ENST00000378156.9 link	c.3292G>A	p.Ala1098Thr	missense_variant	Exon 23 of 30	1	NM_015102.5	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7 link	n.*2193G>A		non_coding_transcript_exon_variant	Exon 20 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.*1103G>A		non_coding_transcript_exon_variant	Exon 26 of 33	2		ENSP00000423747.1	O75161-2
NPHP4	ENST00000378169.7 link	n.*2193G>A		3_prime_UTR_variant	Exon 20 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.*1103G>A		3_prime_UTR_variant	Exon 26 of 33	2		ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000686

AC:

171

AN:

249248

AF XY:

0.000717

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.00103

AC:

1506

AN:

1461586

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

740

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33476

American (AMR)

AF:

0.000313

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000394

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00126

AC:

1400

AN:

1111772

Other (OTH)

AF:

0.000679

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

148

223

297

371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.000722

AC:

110

AN:

152302

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41576

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00113

Hom.:

Bravo

AF:

0.000706

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000237

AC:

ESP6500EA

AF:

0.000949

AC:

ExAC

AF:

0.000793

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Senior-Loken syndrome 4;C1847013:Nephronophthisis 4

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis

Uncertain:1

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1098 of the NPHP4 protein (p.Ala1098Thr). This variant is present in population databases (rs41280798, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nephronophthisis and focal segmental glomerulosclerosis (PMID: 15776426, 26346198). ClinVar contains an entry for this variant (Variation ID: 500975). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NPHP4 protein function. Experimental studies have shown that this missense change does not substantially affect NPHP4 function (PMID: 21546380). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Jul 06, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nephronophthisis 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.029

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.11

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.42

M_CAP

Benign

0.0073

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.79

PhyloP100

-1.2

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.33

Sift

Benign

0.47

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.63

MVP

0.40

MPC

0.062

ClinPred

0.0054

GERP RS

-9.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.24

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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