1-5875004-T-C

Variant names:

• chr1-5875004-T-C
• rs187947581
• NM_015102.5:c.2914A>G

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.2914A>G​(p.Ser972Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,612,104 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S972R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (16 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.58
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010935932).
• BP6: Variant 1-5875004-T-C is Benign according to our data. Variant chr1-5875004-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195610.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 = 0.0032 (487/152284) while in subpopulation NFE AF = 0.0045 (306/68022). AF 95% confidence interval is 0.00408. There are 2 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2914A>G	p.Ser972Gly	missense	Exon 21 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.1378A>G	p.Ser460Gly	missense	Exon 17 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1375A>G	p.Ser459Gly	missense	Exon 18 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.2914A>G	p.Ser972Gly	missense	Exon 21 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*1815A>G		non_coding_transcript_exon	Exon 18 of 27	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.*725A>G		non_coding_transcript_exon	Exon 24 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.00320 AC: 487 AN: 152166 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00278 AC: 689 AN: 247510 AF XY: 0.00284

Gnomad AFR exome AF: 0.000838

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00958

Gnomad NFE exome AF: 0.00387

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.00401 AC: 5856 AN: 1459820 Hom.: 16 Cov.: 33 AF XY: 0.00382 AC XY: 2774 AN XY: 726248

African (AFR) AF: 0.000568 AC: 19 AN: 33474

American (AMR) AF: 0.000626 AC: 28 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86250

European-Finnish (FIN) AF: 0.00872 AC: 450 AN: 51582

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00460 AC: 5115 AN: 1111840

Other (OTH) AF: 0.00313 AC: 189 AN: 60360

GnomAD4 genome AF: 0.00320 AC: 487 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00326 AC XY: 243 AN XY: 74462

African (AFR) AF: 0.000746 AC: 31 AN: 41562

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0121 AC: 129 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00450 AC: 306 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00339 Hom.: 4

Bravo AF: 0.00232

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00362 AC: 31

ExAC AF: 0.00273 AC: 331

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

May 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHP4: BS2

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:1

Jan 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Senior-Loken syndrome 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Nephronophthisis Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nephronophthisis 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.028
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.6
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.62
Sift	Benign	0.13	T
Sift4G	Benign	0.085	T
Polyphen		0.65	P
Vest4		0.27
MVP		0.92
MPC		0.061
ClinPred		0.028	T
GERP RS		3.7
Varity_R		0.16
gMVP		0.66
Mutation Taster		=94/6	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: rs187947581; hg19: chr1-5935064;