Genetic Variant NPHP4:p.Glu989Lys (chr1-5874953-C-T) – ACMG Classification: Uncertain_significance (0 pts)

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36386117).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000617 (94/152240) while in subpopulation AFR AF= 0.00168 (70/41548). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5 link	c.2965G>A	p.Glu989Lys	missense_variant	Exon 21 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NPHP4	ENST00000378156.9 link	c.2965G>A	p.Glu989Lys	missense_variant	Exon 21 of 30	1	NM_015102.5	ENSP00000367398.4	O75161-1
NPHP4	ENST00000378169.7 link	n.*1866G>A		non_coding_transcript_exon_variant	Exon 18 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.*776G>A		non_coding_transcript_exon_variant	Exon 24 of 33	2		ENSP00000423747.1	O75161-2
NPHP4	ENST00000378169.7 link	n.*1866G>A		3_prime_UTR_variant	Exon 18 of 27	1		ENSP00000367411.3	D6RA06
NPHP4	ENST00000489180.6 link	n.*776G>A		3_prime_UTR_variant	Exon 24 of 33	2		ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

94

AN:

152122

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000430

AC:

107

AN:

248728

Hom.:

0

AF XY:

0.000415

AC XY:

56

AN XY:

134998

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000261

AC:

381

AN:

1461218

Hom.:

1

Cov.:

33

AF XY:

0.000275

AC XY:

200

AN XY:

726884

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000777

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000617

AC:

94

AN:

152240

Hom.:

0

Cov.:

32

AF XY:

0.000524

AC XY:

39

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00168

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000257

Hom.:

0

Bravo

AF:

0.000831

ESP6500AA

AF:

0.00162

AC:

7

ESP6500EA

AF:

0.000353

AC:

3

ExAC

AF:

0.000412

AC:

50

Asia WGS

AF:

0.00173

AC:

6

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with a clinical diagnosis of Senior-Loken syndrome, in cis with another missense allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32865313) -

Mar 15, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHP4 p.Glu989Lys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs116606479), ClinVar (classified as a VUS by Invitae, EGL Genetics, GeneDx and Illumina), and in LOVD 3.0 (variant is listed as likely benign). The variant was also identified in control databases in 125 of 280094 chromosomes at a frequency of 0.000446 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 50 of 24192 chromosomes (freq: 0.002067), Other in 8 of 7136 chromosomes (freq: 0.001121), South Asian in 17 of 30602 chromosomes (freq: 0.000556), Latino in 17 of 35368 chromosomes (freq: 0.000481), European (non-Finnish) in 31 of 128312 chromosomes (freq: 0.000242) and East Asian in 2 of 19532 chromosomes (freq: 0.000102), but not in the Ashkenazi Jewish, and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu989 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Nephronophthisis 4

Uncertain:2

Jan 15, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nephronophthisis

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPHP4-related disorder

Uncertain:1

May 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHP4 c.2965G>A variant is predicted to result in the amino acid substitution p.Glu989Lys. This variant along with two other NPHP4 variants (c.2951C>T, p.Thr984Met and c.2203C>T, p.Arg735Trp) were reported in an individual with Senior–Løken syndrome (Sallum et al. 2020. PubMed ID: 32865313). This variant was also reported as uncertain significance with c.2203C>T (p.Arg735Trp) in individuals with chronic kidney disease and nephronophthisis (Al-Hamed et al. 2022. PubMed ID: 36177613; Tables S2 and S3, König et al. 2022. PubMed ID: 36090483). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Senior-Loken syndrome 4

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.035

T

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

25

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Uncertain

0.94

D

M_CAP

Uncertain

0.18

D

MetaRNN

Benign

0.36

T

MetaSVM

Uncertain

0.79

D

MutationAssessor

Uncertain

2.9

M

PrimateAI

Uncertain

0.63

T

PROVEAN

Uncertain

-3.0

D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.011

D

Sift4G

Uncertain

0.0050

D

Polyphen

1.0

D

Vest4

0.88

MVP

0.95

MPC

0.41

ClinPred

0.036

T

GERP RS

5.0

Varity_R

0.40

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr1-5874953-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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