chr3-132690657-A-G

Position:

chr3-132690657-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153240.5(NPHP3):c.2571-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,613,306 control chromosomes in the GnomAD database, including 1,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 102 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1405 hom. )

Consequence

NPHP3
NM_153240.5 splice_region, intron

Scores

Splicing: ADA: 0.00001937

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.191

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:

NPHP3 (HGNC:):

NPHP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 3-132690657-A-G is Benign according to our data. Variant chr3-132690657-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 96512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132690657-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0288 (4392/152290) while in subpopulation NFE AF= 0.0475 (3232/68002). AF 95% confidence interval is 0.0462. There are 102 homozygotes in gnomad4. There are 2022 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 102 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP3	NM_153240.5 linkuse as main transcript	c.2571-7T>C		splice_region_variant, intron_variant		ENST00000337331.10	NP_694972.3	Q7Z494-1
NPHP3-ACAD11	NR_037804.1 linkuse as main transcript	n.2577-7T>C		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10 linkuse as main transcript	c.2571-7T>C		splice_region_variant, intron_variant		1	NM_153240.5	ENSP00000338766.5		Q7Z494-1

Frequencies

GnomAD3 genomes

AF:

0.0289

AC:

4397

AN:

152172

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00784

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0398

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00952

Gnomad FIN

AF:

0.0297

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0475

Gnomad OTH

AF:

0.0162

GnomAD3 exomes

AF:

0.0304

AC:

7637

AN:

251272

Hom.:

187

AF XY:

0.0308

AC XY:

4189

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00715

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.0386

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.0302

Gnomad NFE exome

AF:

0.0494

Gnomad OTH exome

AF:

0.0307

GnomAD4 exome

AF:

0.0406

AC:

59340

AN:

1461016

Hom.:

1405

Cov.:

AF XY:

0.0397

AC XY:

28871

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.00663

Gnomad4 AMR exome

AF:

0.0108

Gnomad4 ASJ exome

AF:

0.0387

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0110

Gnomad4 FIN exome

AF:

0.0308

Gnomad4 NFE exome

AF:

0.0475

Gnomad4 OTH exome

AF:

0.0344

GnomAD4 genome

AF:

0.0288

AC:

4392

AN:

152290

Hom.:

102

Cov.:

AF XY:

0.0272

AC XY:

2022

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00784

Gnomad4 AMR

AF:

0.0166

Gnomad4 ASJ

AF:

0.0398

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00952

Gnomad4 FIN

AF:

0.0297

Gnomad4 NFE

AF:

0.0475

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0410

Hom.:

Bravo

AF:

0.0280

Asia WGS

AF:

0.00520

AC:

AN:

3476

EpiCase

AF:

0.0481

EpiControl

AF:

0.0487

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2016	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. -
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	-	- -

Renal-hepatic-pancreatic dysplasia 1

Benign:1

Benign, 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 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. -

NPHP3-related Meckel-like syndrome

Benign:1

Likely benign, 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 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2019

- -

Nephronophthisis 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.51

DANN

Benign

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000019

dbscSNV1_RF

Benign

0.0

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