rs78527322

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_153240.5(NPHP3):c.450G>A(p.Ala150Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,602,544 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 32 hom. )

Consequence

NPHP3
NM_153240.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.224

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 3-132719774-C-T is Benign according to our data. Variant chr3-132719774-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 167380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132719774-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.224 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0086 (1306/151946) while in subpopulation AFR AF= 0.027 (1120/41460). AF 95% confidence interval is 0.0257. There are 16 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP3	NM_153240.5 link	c.450G>A	p.Ala150Ala	synonymous_variant	Exon 2 of 27	ENST00000337331.10	NP_694972.3	Q7Z494-1
NPHP3-ACAD11	NR_037804.1 link	n.554G>A		non_coding_transcript_exon_variant	Exon 2 of 45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10 link	c.450G>A	p.Ala150Ala	synonymous_variant	Exon 2 of 27	1	NM_153240.5	ENSP00000338766.5		Q7Z494-1

Frequencies

GnomAD3 genomes

AF:

0.00860

AC:

1305

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00524

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.0000956

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00338

AC:

846

AN:

250054

Hom.:

AF XY:

0.00285

AC XY:

386

AN XY:

135240

show subpopulations

Gnomad AFR exome

AF:

0.0289

Gnomad AMR exome

AF:

0.00366

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00168

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00182

AC:

2647

AN:

1450598

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1281

AN XY:

721704

show subpopulations

Gnomad4 AFR exome

AF:

0.0304

Gnomad4 AMR exome

AF:

0.00388

Gnomad4 ASJ exome

AF:

0.00314

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00180

Gnomad4 FIN exome

AF:

0.000530

Gnomad4 NFE exome

AF:

0.000868

Gnomad4 OTH exome

AF:

0.00299

GnomAD4 genome

AF:

0.00860

AC:

1306

AN:

151946

Hom.:

Cov.:

AF XY:

0.00831

AC XY:

617

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0270

Gnomad4 AMR

AF:

0.00523

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.0000956

Gnomad4 NFE

AF:

0.00106

Gnomad4 OTH

AF:

0.00617

Alfa

AF:

0.00422

Hom.:

Bravo

AF:

0.0102

Asia WGS

AF:

0.00434

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 29, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2016

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. -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Renal-hepatic-pancreatic dysplasia 1

Benign:1

Jan 12, 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. -

Kidney disorder

Benign:1

Feb 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NPHP3-related Meckel-like syndrome

Benign:1

Jan 12, 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. -

Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 3

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.81

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