NM_153240.5:c.65C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_153240.5(NPHP3):c.65C>T(p.Ala22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,578,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A22A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NPHP3
NM_153240.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.37

Publications

0 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-AS1 (HGNC:24129): (NPHP3 antisense RNA 1)

NPHP3-AS1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.31020826).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP3	NM_153240.5	MANE Select	c.65C>T	p.Ala22Val	missense	Exon 1 of 27	NP_694972.3
NPHP3-AS1	NR_002811.2		n.542G>A		non_coding_transcript_exon	Exon 1 of 11
NPHP3-ACAD11	NR_037804.1		n.169C>T		non_coding_transcript_exon	Exon 1 of 45

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.65C>T	p.Ala22Val	missense	Exon 1 of 27	ENSP00000338766.5	Q7Z494-1
NPHP3	ENST00000383282.3	TSL:1	c.65C>T	p.Ala22Val	missense	Exon 1 of 2	ENSP00000372769.2	Q7Z494-7
NPHP3-AS1	ENST00000489343.5	TSL:1	n.542G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000140

AC:

AN:

206718

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.000100

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000272

Gnomad OTH exome

AF:

0.000393

GnomAD4 exome

AF:

0.000130

AC:

186

AN:

1426462

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

710028

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30804

American (AMR)

AF:

0.0000234

AC:

AN:

42774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25480

East Asian (EAS)

AF:

0.00

AC:

AN:

37268

South Asian (SAS)

AF:

0.00

AC:

AN:

84032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38296

Middle Eastern (MID)

AF:

0.000992

AC:

AN:

5038

European-Non Finnish (NFE)

AF:

0.000162

AC:

179

AN:

1103414

Other (OTH)

AF:

0.0000168

AC:

AN:

59356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.000164

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000141

AC:

ExAC

AF:

0.000130

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Nephronophthisis (1)

Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 (1)

NPHP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.31

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

-0.34

PhyloP100

2.4

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.44

REVEL

Benign

0.29

Sift

Benign

0.12

Sift4G

Uncertain

0.026

Polyphen

0.87

Vest4

0.16

MVP

0.85

MPC

0.19

ClinPred

0.10

GERP RS

2.6

PromoterAI

-0.093

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.44

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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