rs115526767

Positions:

chr1-5864458-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000378156.9(NPHP4):c.3876C>T(p.Gly1292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,605,318 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0096 ( 14 hom., cov: 33)

Exomes 𝑓: 0.016 ( 219 hom. )

Consequence

NPHP4
ENST00000378156.9 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.52

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-5864458-G-A is Benign according to our data. Variant chr1-5864458-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5864458-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.52 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0096 (1463/152322) while in subpopulation NFE AF= 0.0161 (1095/68020). AF 95% confidence interval is 0.0153. There are 14 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.3876C>T	p.Gly1292=	synonymous_variant	28/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.3876C>T	p.Gly1292=	synonymous_variant	28/30	1	NM_015102.5	ENSP00000367398	P2	O75161-1

Frequencies

GnomAD3 genomes

AF:

0.00961

AC:

1463

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00930

AC:

2132

AN:

229252

Hom.:

AF XY:

0.00941

AC XY:

1177

AN XY:

125120

show subpopulations

Gnomad AFR exome

AF:

0.00257

Gnomad AMR exome

AF:

0.00447

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00360

Gnomad FIN exome

AF:

0.00572

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.00953

GnomAD4 exome

AF:

0.0156

AC:

22728

AN:

1452996

Hom.:

219

Cov.:

AF XY:

0.0152

AC XY:

10940

AN XY:

721954

show subpopulations

Gnomad4 AFR exome

AF:

0.00258

Gnomad4 AMR exome

AF:

0.00455

Gnomad4 ASJ exome

AF:

0.00220

Gnomad4 EAS exome

AF:

0.0000764

Gnomad4 SAS exome

AF:

0.00395

Gnomad4 FIN exome

AF:

0.00700

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.00960

AC:

1463

AN:

152322

Hom.:

Cov.:

AF XY:

0.00906

AC XY:

675

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00298

Gnomad4 AMR

AF:

0.00816

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00725

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.0142

Hom.:

Bravo

AF:

0.00969

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Kidney disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Senior-Loken syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Nephronophthisis 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.51

DANN

Benign

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over