rs141477666

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_153240.5(NPHP3):c.1189C>T(p.Arg397Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00513 in 1,613,692 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R397H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 31 hom. )

Consequence

NPHP3
NM_153240.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 3.73

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:):

NPHP3-ACAD11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040944546).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00322 (490/152320) while in subpopulation NFE AF= 0.00513 (349/68024). AF 95% confidence interval is 0.00469. There are 2 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP3	NM_153240.5 linkuse as main transcript	c.1189C>T	p.Arg397Cys	missense_variant	7/27	ENST00000337331.10
NPHP3-ACAD11	NR_037804.1 linkuse as main transcript	n.1293C>T		non_coding_transcript_exon_variant	7/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP3	ENST00000337331.10 linkuse as main transcript	c.1189C>T	p.Arg397Cys	missense_variant	7/27	1	NM_153240.5	P1	Q7Z494-1

Frequencies

GnomAD3 genomes

AF:

0.00322

AC:

490

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00773

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00513

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00304

AC:

764

AN:

251380

Hom.:

AF XY:

0.00291

AC XY:

396

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00638

Gnomad NFE exome

AF:

0.00497

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00533

AC:

7785

AN:

1461372

Hom.:

Cov.:

AF XY:

0.00513

AC XY:

3730

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.000926

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00515

Gnomad4 NFE exome

AF:

0.00644

Gnomad4 OTH exome

AF:

0.00432

GnomAD4 genome

AF:

0.00322

AC:

490

AN:

152320

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00773

Gnomad4 NFE

AF:

0.00513

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00416

Hom.:

Bravo

AF:

0.00286

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00330

AC:

401

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00382

EpiControl

AF:

0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2022	Variant summary: NPHP3 c.1189C>T (p.Arg397Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251380 control chromosomes, including 4 homozygotes. The variant was predominantly found within the Non-Finnish European subpopulation at a frequency of 0.005. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in NPHP3 causing Joubert Syndrome and Related Disorders phenotype (0.0004), strongly suggesting that the variant is a benign polymorphism. c.1189C>T has been reported in the literature in the heterozygous state in individuals affected with retinal- or renal dysorders (e.g. Tiwari_2016, Arno_2017, Hoefele_2007), however in these cases other (potentially) pathogenic variants were also described, including a homozygous deletion variant in NPHP1 that was found in two siblings affected with nephronophthisis (Hoefele_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed this variant since 2014: one submitter classified the variant as of uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. -

Renal-hepatic-pancreatic dysplasia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

NPHP3-related Meckel-like syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Nephronophthisis 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Nephronophthisis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2020

This variant is associated with the following publications: (PMID: 27392076, 17855640, 23188109) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.0071

BayesDel_noAF

Pathogenic

0.22

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.041

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.025

Polyphen

0.99

Vest4

0.78

MVP

0.87

MPC

0.59

ClinPred

0.029

GERP RS

4.8

Varity_R

0.20

gMVP

0.52

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