NM_153240.5:c.3550G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_153240.5(NPHP3):c.3550G>A(p.Ala1184Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00877 in 1,613,890 control chromosomes in the GnomAD database, including 99 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 0.0075 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 87 hom. )

Consequence

NPHP3
NM_153240.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

NPHP3 (HGNC:7907): (nephrocystin 3) This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]

NPHP3 links:

NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

NPHP3-ACAD11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011167735).

BP6

Variant 3-132684574-C-T is Benign according to our data. Variant chr3-132684574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=6, Uncertain_significance=2}. Variant chr3-132684574-C-T is described in Lovd as [Likely_benign]. Variant chr3-132684574-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00749 (1140/152260) while in subpopulation NFE AF= 0.0113 (770/68002). AF 95% confidence interval is 0.0107. There are 12 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP3	NM_153240.5 link	c.3550G>A	p.Ala1184Thr	missense_variant	Exon 24 of 27	ENST00000337331.10	NP_694972.3	Q7Z494-1
NPHP3-ACAD11	NR_037804.1 link	n.3556G>A		non_coding_transcript_exon_variant	Exon 23 of 45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10 link	c.3550G>A	p.Ala1184Thr	missense_variant	Exon 24 of 27	1	NM_153240.5	ENSP00000338766.5		Q7Z494-1
NPHP3-ACAD11	ENST00000632629.1 link	c.196G>A	p.Ala66Thr	missense_variant	Exon 1 of 5	2		ENSP00000488520.1		A0A0J9YXS1

Frequencies

GnomAD3 genomes

AF:

0.00749

AC:

1140

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0103

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00823

AC:

2065

AN:

250872

Hom.:

AF XY:

0.00868

AC XY:

1178

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00983

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.00931

GnomAD4 exome

AF:

0.00890

AC:

13008

AN:

1461630

Hom.:

Cov.:

AF XY:

0.00924

AC XY:

6721

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.0212

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0103

Gnomad4 FIN exome

AF:

0.0138

Gnomad4 NFE exome

AF:

0.00911

Gnomad4 OTH exome

AF:

0.00942

GnomAD4 genome

AF:

0.00749

AC:

1140

AN:

152260

Hom.:

Cov.:

AF XY:

0.00767

AC XY:

571

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00144

Gnomad4 AMR

AF:

0.00372

Gnomad4 ASJ

AF:

0.0234

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.0105

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00611

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.00863

AC:

1048

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00872

EpiControl

AF:

0.00806

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 30, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 26, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHP3: BS1, BS2 -

May 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NPHP3-related Meckel-like syndrome

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Bardet-Biedl syndrome

Uncertain:1

Jun 02, 2023

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Renal-hepatic-pancreatic dysplasia 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

3.8

.;H

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

.;D

Vest4

0.94

MVP

0.91

MPC

0.72

ClinPred

0.091

GERP RS

4.7

Varity_R

0.74

gMVP

0.70

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