rs12142270

chr1-5986204-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015102.5(NPHP4):c.86C>T(p.Thr29Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,613,662 control chromosomes in the GnomAD database, including 922 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T29T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.042 (187 hom., cov: 33)
  • Exomes 𝑓: 0.027 (735 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.911

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019364357).
• BP6: Variant 1-5986204-G-A is Benign according to our data. Variant chr1-5986204-G-A is described in ClinVar as [Benign]. Clinvar id is 260561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5986204-G-A is described in Lovd as [Benign]. Variant chr1-5986204-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.86C>T	p.Thr29Met	missense_variant	2/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.86C>T	p.Thr29Met	missense_variant	2/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6374 AN: 152154 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0432

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0441

GnomAD3 exomes AF: 0.0291 AC: 7253 AN: 248848 Hom.: 179 AF XY: 0.0286 AC XY: 3864 AN XY: 135072

Gnomad AFR exome AF: 0.0877

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0320

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0274

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0272 AC: 39757 AN: 1461390 Hom.: 735 Cov.: 31 AF XY: 0.0270 AC XY: 19635 AN XY: 726968

Gnomad4 AFR exome AF: 0.0913

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0332

Gnomad4 FIN exome AF: 0.0445

Gnomad4 NFE exome AF: 0.0253

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0419 AC: 6374 AN: 152272 Hom.: 187 Cov.: 33 AF XY: 0.0415 AC XY: 3089 AN XY: 74450

Gnomad4 AFR AF: 0.0863

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0268

Gnomad4 FIN AF: 0.0432

Gnomad4 NFE AF: 0.0248

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0281 Hom.: 159

Bravo AF: 0.0419

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.0781 AC: 320

ESP6500EA AF: 0.0251 AC: 210

ExAC AF: 0.0320 AC: 3874

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Nephronophthisis 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Senior-Loken syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2018

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.81	N;.
REVEL	Benign	0.25
Sift	Uncertain	0.010	D;.
Sift4G	Uncertain	0.027	D;D
Polyphen		0.99	D;.
Vest4		0.21
MPC		0.081
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.050
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs12142270; hg19: chr1-6046264; COSMIC: COSV65394927;