Genetic Variant NPHP3:p.Ala22Glu (chr3-132722291-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153240.5(NPHP3):c.65C>A(p.Ala22Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,426,462 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

NPHP3
NM_153240.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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>A	p.Ala22Glu	missense	Exon 1 of 27	NP_694972.3
NPHP3-AS1	NR_002811.2		n.542G>T		non_coding_transcript_exon	Exon 1 of 11
NPHP3-ACAD11	NR_037804.1		n.169C>A		non_coding_transcript_exon	Exon 1 of 45

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.65C>A	p.Ala22Glu	missense	Exon 1 of 27	ENSP00000338766.5
NPHP3	ENST00000383282.3	TSL:1	c.65C>A	p.Ala22Glu	missense	Exon 1 of 2	ENSP00000372769.2
NPHP3-AS1	ENST00000489343.5	TSL:1	n.542G>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1426462

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710028

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30804

American (AMR)

AF:

0.00

AC:

AN:

42774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25480

East Asian (EAS)

AF:

0.00

AC:

AN:

37266

South Asian (SAS)

AF:

0.00

AC:

AN:

84034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5038

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103414

Other (OTH)

AF:

0.00

AC:

AN:

59356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.93

MetaRNN

Uncertain

0.46

MetaSVM

Uncertain

-0.092

MutationAssessor

Benign

0.0

PhyloP100

2.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.19

REVEL

Benign

0.28

Sift

Benign

0.19

Sift4G

Uncertain

0.045

Polyphen

0.59

Vest4

0.27

MutPred

0.42

Gain of glycosylation at Y20 (P = 0.0031)

MVP

0.88

MPC

0.21

ClinPred

0.31

GERP RS

2.6

PromoterAI

0.054

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.56

Mutation Taster

=74/26

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over