dbSNP rs571655: NPHP4:p.Glu618Gln (chr1-5905395-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

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

The NM_015102.5(NPHP4):c.1852G>C(p.Glu618Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. E618K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

NPHP4
NM_015102.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.89

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39063627).

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.1852G>C	p.Glu618Gln	missense	Exon 15 of 30	NP_055917.1
NPHP4	NM_001291594.2		c.316G>C	p.Glu106Gln	missense	Exon 11 of 26	NP_001278523.1
NPHP4	NM_001291593.2		c.313G>C	p.Glu105Gln	missense	Exon 12 of 27	NP_001278522.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.1852G>C	p.Glu618Gln	missense	Exon 15 of 30	ENSP00000367398.4
NPHP4	ENST00000378169.7	TSL:1	n.*753G>C		non_coding_transcript_exon	Exon 12 of 27	ENSP00000367411.3
NPHP4	ENST00000489180.6	TSL:2	n.1849G>C		non_coding_transcript_exon	Exon 15 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

0.11

Eigen_PC

Benign

-0.022

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.69

M_CAP

Benign

0.076

MetaRNN

Benign

0.39

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.4

PhyloP100

3.9

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.37

Sift

Benign

0.13

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.41

MutPred

0.14

Gain of helix (P = 0.062)

MVP

0.92

MPC

0.28

ClinPred

0.83

GERP RS

3.6

Varity_R

0.083

gMVP

0.36

Mutation Taster

=90/10

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