rs12093500

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015102.5(NPHP4):c.1631C>G(p.Ala544Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00587 in 1,609,506 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 141 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 172 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.46

Publications

4 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, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016799569).

BP6

Variant 1-5905764-G-C is Benign according to our data. Variant chr1-5905764-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

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.1631C>G	p.Ala544Gly	missense	Exon 14 of 30	NP_055917.1	O75161-1
NPHP4	NM_001291594.2		c.95C>G	p.Ala32Gly	missense	Exon 10 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.92C>G	p.Ala31Gly	missense	Exon 11 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.1631C>G	p.Ala544Gly	missense	Exon 14 of 30	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7	TSL:1	n.*532C>G		non_coding_transcript_exon	Exon 11 of 27	ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6	TSL:2	n.1628C>G		non_coding_transcript_exon	Exon 14 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes

AF:

0.0261

AC:

3976

AN:

152124

Hom.:

142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0877

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0140

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.0202

GnomAD2 exomes

AF:

0.00771

AC:

1850

AN:

239812

AF XY:

0.00628

show subpopulations

Gnomad AFR exome

AF:

0.0944

Gnomad AMR exome

AF:

0.00826

Gnomad ASJ exome

AF:

0.00112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00665

GnomAD4 exome

AF:

0.00375

AC:

5462

AN:

1457264

Hom.:

172

Cov.:

AF XY:

0.00345

AC XY:

2501

AN XY:

724424

show subpopulations

African (AFR)

AF:

0.0943

AC:

3145

AN:

33366

American (AMR)

AF:

0.00896

AC:

395

AN:

44106

Ashkenazi Jewish (ASJ)

AF:

0.00123

AC:

AN:

25984

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.000410

AC:

AN:

85288

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53134

Middle Eastern (MID)

AF:

0.0127

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00120

AC:

1332

AN:

1109820

Other (OTH)

AF:

0.00745

AC:

449

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

266

532

799

1065

1331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.0261

AC:

3979

AN:

152242

Hom.:

141

Cov.:

AF XY:

0.0243

AC XY:

1813

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0875

AC:

3633

AN:

41520

American (AMR)

AF:

0.0139

AC:

213

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

68030

Other (OTH)

AF:

0.0199

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

193

385

578

770

963

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.00492

Hom.:

Bravo

AF:

0.0299

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0787

AC:

306

ESP6500EA

AF:

0.00169

AC:

ExAC

AF:

0.00857

AC:

1035

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Kidney disorder (1)

Nephronophthisis (1)

Nephronophthisis 4 (1)

Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.5

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.062

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.7

PhyloP100

1.5

PrimateAI

Benign

0.32

PROVEAN

Benign

0.41

REVEL

Benign

0.25

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.039

MVP

0.77

MPC

0.064

ClinPred

0.0018

GERP RS

4.5

Varity_R

0.037

gMVP

0.31

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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