rs190940697

Positions:

• chr1-5947199-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001291594.2(NPHP4):​c.-343C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,613,796 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (10 hom.)
• Consequence: NPHP4 NM_001291594.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.98

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013156593).
• BP6: Variant 1-5947199-G-A is Benign according to our data. Variant chr1-5947199-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281181.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}. Variant chr1-5947199-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00135 (205/152208) while in subpopulation AMR AF= 0.00588 (90/15298). AF 95% confidence interval is 0.0049. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.1024C>T	p.Arg342Cys	missense_variant	9/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.1024C>T	p.Arg342Cys	missense_variant	9/30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*98C>T		non_coding_transcript_exon_variant	8/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.1024C>T		non_coding_transcript_exon_variant	9/33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*98C>T		3_prime_UTR_variant	8/27	1		ENSP00000367411.3

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00164 AC: 409 AN: 249242 Hom.: 1 AF XY: 0.00197 AC XY: 266 AN XY: 135218

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00542

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.00115 AC: 1685 AN: 1461588 Hom.: 10 Cov.: 31 AF XY: 0.00138 AC XY: 1001 AN XY: 727066

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00583

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000755

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.00167 AC XY: 124 AN XY: 74430

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00122 Hom.: 1

Bravo AF: 0.00131

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.00138 AC: 167

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Senior-Loken syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Kidney disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 16, 2017

- -

Nephronophthisis 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 29, 2016

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

NPHP4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.43
MVP		0.98
MPC		0.10
ClinPred		0.059	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.52

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: rs190940697; hg19: chr1-6007259;