3-132690611-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_153240.5(NPHP3):c.2610G>A(p.Pro870Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,574 control chromosomes in the GnomAD database, including 835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P870P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.043 ( 268 hom., cov: 32)

Exomes 𝑓: 0.021 ( 567 hom. )

Consequence

NPHP3
NM_153240.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.21

Publications

11 publications found

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 was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 3-132690611-C-T is Benign according to our data. Variant chr3-132690611-C-T is described in ClinVar as Benign. ClinVar VariationId is 96513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.21 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153240.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.2610G>A	p.Pro870Pro	synonymous	Exon 19 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.2616G>A		non_coding_transcript_exon	Exon 18 of 45

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.2610G>A	p.Pro870Pro	synonymous	Exon 19 of 27	ENSP00000338766.5
NPHP3	ENST00000465756.5	TSL:5	n.*518G>A		non_coding_transcript_exon	Exon 17 of 25	ENSP00000419907.1
NPHP3-ACAD11	ENST00000471702.2	TSL:2	n.*601G>A		non_coding_transcript_exon	Exon 18 of 45	ENSP00000419763.1

Frequencies

GnomAD3 genomes

AF:

0.0427

AC:

6497

AN:

152018

Hom.:

268

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.0654

Gnomad SAS

AF:

0.0491

Gnomad FIN

AF:

0.00613

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0388

GnomAD2 exomes

AF:

0.0282

AC:

7092

AN:

251386

AF XY:

0.0279

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.0669

Gnomad FIN exome

AF:

0.00642

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0210

GnomAD4 exome

AF:

0.0206

AC:

30107

AN:

1461438

Hom.:

567

Cov.:

AF XY:

0.0211

AC XY:

15339

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.104

AC:

3466

AN:

33456

American (AMR)

AF:

0.0134

AC:

600

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0209

AC:

546

AN:

26120

East Asian (EAS)

AF:

0.0454

AC:

1801

AN:

39672

South Asian (SAS)

AF:

0.0464

AC:

4004

AN:

86240

European-Finnish (FIN)

AF:

0.00670

AC:

358

AN:

53414

Middle Eastern (MID)

AF:

0.0239

AC:

138

AN:

5762

European-Non Finnish (NFE)

AF:

0.0158

AC:

17578

AN:

1111670

Other (OTH)

AF:

0.0268

AC:

1616

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1487

2975

4462

5950

7437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

774

1548

2322

3096

3870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0429

AC:

6520

AN:

152136

Hom.:

268

Cov.:

AF XY:

0.0413

AC XY:

3075

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.103

AC:

4285

AN:

41454

American (AMR)

AF:

0.0202

AC:

309

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3472

East Asian (EAS)

AF:

0.0654

AC:

339

AN:

5184

South Asian (SAS)

AF:

0.0491

AC:

237

AN:

4822

European-Finnish (FIN)

AF:

0.00613

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1123

AN:

67996

Other (OTH)

AF:

0.0393

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

305

610

915

1220

1525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0235

Hom.:

282

Bravo

AF:

0.0464

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

EpiCase

AF:

0.0145

EpiControl

AF:

0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 15, 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.

Oct 08, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

NPHP3-related Meckel-like syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nephronophthisis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nephronophthisis 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.89

(source)

DANN

Benign

0.37

PhyloP100

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over