1-5874534-G-A

Position:

chr1-5874534-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_015102.5(NPHP4):c.3168C>T(p.His1056His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000953 in 1,595,674 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 2 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.0270

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:

NPHP4 (HGNC:):

NPHP4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 1-5874534-G-A is Benign according to our data. Variant chr1-5874534-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288722.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr1-5874534-G-A is described in Lovd as [Likely_benign]. Variant chr1-5874534-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.027 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5 linkuse as main transcript	c.3168C>T	p.His1056His	synonymous_variant	22/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPHP4	ENST00000378156.9 linkuse as main transcript	c.3168C>T	p.His1056His	synonymous_variant	22/30	1	NM_015102.5	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7 linkuse as main transcript	n.*2069C>T		non_coding_transcript_exon_variant	19/27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 linkuse as main transcript	n.*979C>T		non_coding_transcript_exon_variant	25/33	2		ENSP00000423747.1	O75161-2
NPHP4	ENST00000378169.7 linkuse as main transcript	n.*2069C>T		3_prime_UTR_variant	19/27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 linkuse as main transcript	n.*979C>T		3_prime_UTR_variant	25/33	2		ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes

AF:

0.000755

AC:

115

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000705

AC:

156

AN:

221336

Hom.:

AF XY:

0.000665

AC XY:

AN XY:

120288

show subpopulations

Gnomad AFR exome

AF:

0.0000807

Gnomad AMR exome

AF:

0.000441

Gnomad ASJ exome

AF:

0.00334

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000701

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000903

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.000973

AC:

1405

AN:

1443330

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

693

AN XY:

715898

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.000401

Gnomad4 ASJ exome

AF:

0.00285

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.000698

Gnomad4 FIN exome

AF:

0.000116

Gnomad4 NFE exome

AF:

0.00108

Gnomad4 OTH exome

AF:

0.000855

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152344

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000961

Hom.:

Bravo

AF:

0.000665

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NPHP4: BP4, BP7 -

Senior-Loken syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nephronophthisis 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Nephronophthisis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.55

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

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