Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015102.5(NPHP4):c.2031C>T(p.Pro677Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,998 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 26 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.50

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 1-5904729-G-A is Benign according to our data. Variant chr1-5904729-G-A is described in ClinVar as Benign. ClinVar VariationId is 240966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.5 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1541/152304) while in subpopulation AFR AF = 0.0348 (1446/41558). AF 95% confidence interval is 0.0333. There are 26 homozygotes in GnomAd4. There are 707 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 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
NPHP4	NM_015102.5	MANE Select	c.2031C>T	p.Pro677Pro	synonymous	Exon 16 of 30	NP_055917.1
NPHP4	NM_001291594.2		c.495C>T	p.Pro165Pro	synonymous	Exon 12 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.492C>T	p.Pro164Pro	synonymous	Exon 13 of 27	NP_001278522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.2031C>T	p.Pro677Pro	synonymous	Exon 16 of 30	ENSP00000367398.4
NPHP4	ENST00000378169.7	TSL:1	n.*932C>T		non_coding_transcript_exon	Exon 13 of 27	ENSP00000367411.3
NPHP4	ENST00000466897.1	TSL:1	n.108C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000425745.1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1535

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.00240

AC:

599

AN:

249304

AF XY:

0.00165

show subpopulations

Gnomad AFR exome

AF:

0.0331

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00231

GnomAD4 exome

AF:

0.00107

AC:

1566

AN:

1461694

Hom.:

Cov.:

AF XY:

0.000931

AC XY:

677

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.0342

AC:

1146

AN:

33480

American (AMR)

AF:

0.00219

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000185

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000773

AC:

AN:

1111858

Other (OTH)

AF:

0.00315

AC:

190

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

160

240

320

400

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.0101

AC:

1541

AN:

152304

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

707

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0348

AC:

1446

AN:

41558

American (AMR)

AF:

0.00366

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68038

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00525

Hom.:

Bravo

AF:

0.0118

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nephronophthisis (1)

Nephronophthisis 4 (1)

not provided (1)

not specified (1)

Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.57

(source)

DANN

Benign

0.69

PhyloP100

-2.5

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs34373111

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over