Genetic Variant NPHP4:p.Pro85Gln (chr1-5978295-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015102.5(NPHP4):c.254C>A(p.Pro85Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. P85L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

Publications

0 publications found

Variant links:

Genes affected

NPHP4 (HGNC:19104): (nephrocystin 4) This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

NPHP4 Gene-Disease associations (from GenCC):

nephronophthisis 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
Senior-Loken syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
nephronophthisis 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NPHP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0800409).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5 link	c.254C>A	p.Pro85Gln	missense_variant	Exon 3 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NPHP4	ENST00000378156.9 link	c.254C>A	p.Pro85Gln	missense_variant	Exon 3 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7 link	n.254C>A		non_coding_transcript_exon_variant	Exon 3 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6 link	n.254C>A		non_coding_transcript_exon_variant	Exon 3 of 33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456038

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33384

American (AMR)

AF:

0.00

AC:

AN:

43916

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26032

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109664

Other (OTH)

AF:

0.00

AC:

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

3.2

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.074

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.0

L;L

PhyloP100

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.22

N;.

REVEL

Benign

0.14

Sift

Benign

0.19

T;.

Sift4G

Benign

0.28

T;T

Polyphen

0.0040

B;.

Vest4

0.25

MutPred

0.22

Loss of glycosylation at P85 (P = 0.0046);Loss of glycosylation at P85 (P = 0.0046);

MVP

0.70

MPC

0.060

ClinPred

0.039

GERP RS

0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.028

gMVP

0.16

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over