rs190940697

Variant names:

• chr1-5947199-G-A
• rs190940697
• NM_015102.5:c.1024C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015102.5(NPHP4):​c.1024C>T​(p.Arg342Cys) variant causes a missense 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R342H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (10 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.98
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.1024C>T	p.Arg342Cys	missense_variant	Exon 9 of 30	ENST00000378156.9	NP_055917.1

Ensembl

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

GnomAD2 exomes AF: 0.00164 AC: 409 AN: 249242 AF XY: 0.00197

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 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

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.00203 AC: 91 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.00583 AC: 503 AN: 86248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53392

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5744

European-Non Finnish (NFE) AF: 0.000755 AC: 839 AN: 1111802

Other (OTH) AF: 0.00184 AC: 111 AN: 60370

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

African (AFR) AF: 0.000169 AC: 7 AN: 41510

American (AMR) AF: 0.00588 AC: 90 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68024

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00115 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 16, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 4 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 29, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		3.0
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
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs190940697; hg19: chr1-6007259;