3-132686308-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_153240.5(NPHP3):c.3281G>A(p.Arg1094Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000921 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1094W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 0 hom. )

Consequence

NPHP3
NM_153240.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 5.50

Publications

6 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: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000539 (82/152168) while in subpopulation NFE AF = 0.00101 (69/68018). AF 95% confidence interval is 0.000821. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.3281G>A	p.Arg1094Gln	missense	Exon 23 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3287G>A		non_coding_transcript_exon	Exon 22 of 45

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.3281G>A	p.Arg1094Gln	missense	Exon 23 of 27	ENSP00000338766.5	Q7Z494-1
NPHP3	ENST00000971413.1		c.3080G>A	p.Arg1027Gln	missense	Exon 21 of 25	ENSP00000641472.1
NPHP3	ENST00000971412.1		c.2858G>A	p.Arg953Gln	missense	Exon 19 of 23	ENSP00000641471.1

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000493

AC:

124

AN:

251476

AF XY:

0.000530

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000949

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000961

AC:

1405

AN:

1461528

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

634

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00121

AC:

1341

AN:

1111728

Other (OTH)

AF:

0.000613

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

156

208

260

<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:

0.000539

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41508

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00102

Hom.:

Bravo

AF:

0.000604

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Nephronophthisis (1)

Nephronophthisis 3 (1)

not specified (1)

NPHP3-related Meckel-like syndrome (1)

Renal-hepatic-pancreatic dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.22

MetaSVM

Uncertain

0.018

MutationAssessor

Benign

0.85

PhyloP100

5.5

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.56

REVEL

Uncertain

0.40

Sift

Benign

0.083

Sift4G

Uncertain

0.044

Polyphen

0.84

Vest4

0.60

MVP

0.92

MPC

0.70

ClinPred

0.070

GERP RS

5.7

Varity_R

0.15

gMVP

0.18

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: -48

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

Computational scores

Splicing

Publications

Other links and lift over