Genetic Variant NPHP4:p.Pro86Gln (chr1-5978292-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.257C>A(p.Pro86Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. P86L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.850

Publications

6 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=0.16857594).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015102.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP4	NM_015102.5	MANE Select	c.257C>A	p.Pro86Gln	missense	Exon 3 of 30	NP_055917.1
NPHP4	NM_001291593.2		c.-973C>A		5_prime_UTR	Exon 3 of 27	NP_001278522.1
NPHP4	NM_001291594.2		c.-1087-9033C>A		intron	N/A	NP_001278523.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.257C>A	p.Pro86Gln	missense	Exon 3 of 30	ENSP00000367398.4
NPHP4	ENST00000378169.7	TSL:1	n.257C>A		non_coding_transcript_exon	Exon 3 of 27	ENSP00000367411.3
NPHP4	ENST00000489180.6	TSL:2	n.257C>A		non_coding_transcript_exon	Exon 3 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.72

M_CAP

Benign

0.062

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.81

PhyloP100

0.85

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

REVEL

Benign

0.13

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0090

Polyphen

0.35

Vest4

0.36

MutPred

0.29

Loss of glycosylation at P86 (P = 0.0079)

MVP

0.86

MPC

0.10

ClinPred

0.12

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.040

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over