rs145255635

chr1-5905773-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):c.1622C>T(p.Pro541Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,607,132 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P541P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.48

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=0.0057252645).
• BP6: Variant 1-5905773-G-A is Benign according to our data. Variant chr1-5905773-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 282763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00246 (374/152252) while in subpopulation AFR AF= 0.00852 (354/41530). AF 95% confidence interval is 0.00779. There are 3 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.1622C>T	p.Pro541Leu	missense_variant	14/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.1622C>T	p.Pro541Leu	missense_variant	14/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152134 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00855

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000673 AC: 158 AN: 234828 Hom.: 0 AF XY: 0.000550 AC XY: 70 AN XY: 127182

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.000635

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000344 AC: 501 AN: 1454880 Hom.: 3 Cov.: 32 AF XY: 0.000306 AC XY: 221 AN XY: 722982

Gnomad4 AFR exome AF: 0.00894

Gnomad4 AMR exome AF: 0.000708

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.000615

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152252 Hom.: 3 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74466

Gnomad4 AFR AF: 0.00852

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000448 Hom.: 1

Bravo AF: 0.00266

ESP6500AA AF: 0.00854 AC: 33

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.000787 AC: 95

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis 4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 24, 2015

- -

Senior-Loken syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

NPHP4-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	12
Dann	Benign	0.67
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Benign	0.11
Sift	Benign	0.090	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.0010	B;.
Vest4		0.35
MVP		0.84
MPC		0.065
ClinPred		0.019	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.35

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

Other links and lift over

dbSNP: rs145255635; hg19: chr1-5965833;