3-132722196-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_153240.5(NPHP3):c.160G>A(p.Gly54Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,356,536 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. G54E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

NPHP3
NM_153240.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.497

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29866365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP3	NM_153240.5 link	c.160G>A	p.Gly54Arg	missense_variant	Exon 1 of 27	ENST00000337331.10	NP_694972.3	Q7Z494-1
NPHP3-AS1	NR_002811.2 link	n.447C>T		non_coding_transcript_exon_variant	Exon 1 of 11
NPHP3-ACAD11	NR_037804.1 link	n.264G>A		non_coding_transcript_exon_variant	Exon 1 of 45
NPHP3-AS1	NR_152743.1 link	n.447C>T		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10 link	c.160G>A	p.Gly54Arg	missense_variant	Exon 1 of 27	1	NM_153240.5	ENSP00000338766.5		Q7Z494-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1356536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

670872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28246

American (AMR)

AF:

0.00

AC:

AN:

31304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23202

East Asian (EAS)

AF:

0.00

AC:

AN:

31784

South Asian (SAS)

AF:

0.00

AC:

AN:

75312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5002

European-Non Finnish (NFE)

AF:

9.35e-7

AC:

AN:

1069388

Other (OTH)

AF:

0.00

AC:

AN:

56384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nephronophthisis

Uncertain:1

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 54 of the NPHP3 protein (p.Gly54Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 531628). This variant has not been reported in the literature in individuals affected with NPHP3-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.71

T;T

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.50

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.32

N;N

REVEL

Benign

0.20

Sift

Benign

0.10

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;.

Vest4

0.31

MutPred

0.44

Gain of methylation at G54 (P = 0.0053);Gain of methylation at G54 (P = 0.0053);

MVP

0.79

MPC

0.32

ClinPred

0.36

GERP RS

1.0

PromoterAI

0.031

Neutral

(source)

Varity_R

0.041

gMVP

0.10

Mutation Taster

=85/15

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over