1-5905395-C-T

Variant names:

• chr1-5905395-C-T
• rs571655
• NM_015102.5:c.1852G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):​c.1852G>A​(p.Glu618Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0118 in 1,613,372 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (7 hom., cov: 33)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 3.89
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073396564).
• BP6: Variant 1-5905395-C-T is Benign according to our data. Variant chr1-5905395-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00997 (1518/152240) while in subpopulation NFE AF = 0.0144 (981/68012). AF 95% confidence interval is 0.0137. There are 7 homozygotes in GnomAd4. There are 723 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015102.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.1852G>A	p.Glu618Lys	missense	Exon 15 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.316G>A	p.Glu106Lys	missense	Exon 11 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.313G>A	p.Glu105Lys	missense	Exon 12 of 27	NP_001278522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.1852G>A	p.Glu618Lys	missense	Exon 15 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*753G>A		non_coding_transcript_exon	Exon 12 of 27	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.1849G>A		non_coding_transcript_exon	Exon 15 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.00997 AC: 1517 AN: 152122 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0104 AC: 2585 AN: 249266 AF XY: 0.0104

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0120 AC: 17540 AN: 1461132 Hom.: 152 Cov.: 32 AF XY: 0.0119 AC XY: 8680 AN XY: 726796

African (AFR) AF: 0.00370 AC: 124 AN: 33470

American (AMR) AF: 0.00613 AC: 274 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 804 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00308 AC: 266 AN: 86248

European-Finnish (FIN) AF: 0.00942 AC: 503 AN: 53402

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5766

European-Non Finnish (NFE) AF: 0.0131 AC: 14563 AN: 1111342

Other (OTH) AF: 0.0133 AC: 805 AN: 60360

GnomAD4 genome AF: 0.00997 AC: 1518 AN: 152240 Hom.: 7 Cov.: 33 AF XY: 0.00971 AC XY: 723 AN XY: 74444

African (AFR) AF: 0.00308 AC: 128 AN: 41532

American (AMR) AF: 0.00954 AC: 146 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.00943 AC: 100 AN: 10606

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 981 AN: 68012

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0135 Hom.: 52

Bravo AF: 0.00984

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00354 AC: 14

ESP6500EA AF: 0.0148 AC: 124

ExAC AF: 0.0103 AC: 1239

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHP4: BS1, BS2

Nephronophthisis 4 Uncertain:1 Benign:1

Tolun Lab, Human Genetics Laboratory, Bogazici University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Senior-Loken syndrome 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Kidney disorder Benign:1

Mar 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nephronophthisis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0073	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.43
MPC		0.15
ClinPred		0.038	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.48
Mutation Taster		=96/4	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: rs571655; hg19: chr1-5965455;