1-5978259-C-T

Variant names:

• chr1-5978259-C-T
• rs113902159
• NM_015102.5:c.279+11G>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.279+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,601,012 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 29)
  • Exomes 𝑓: 0.00038 (5 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0240
• Publications: 1 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 (BayesDel_noAF=-0.82).
• BP6: Variant 1-5978259-C-T is Benign according to our data. Variant chr1-5978259-C-T is described in ClinVar as Benign. ClinVar VariationId is 260548.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 = 0.00376 (572/152192) while in subpopulation AFR AF = 0.013 (541/41486). AF 95% confidence interval is 0.0121. There are 4 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.279+11G>A		intron_variant	Intron 3 of 29	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.279+11G>A		intron_variant	Intron 3 of 29	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.279+11G>A		intron_variant	Intron 3 of 26	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.279+11G>A		intron_variant	Intron 3 of 32	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152074 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000799 AC: 183 AN: 228980 AF XY: 0.000546

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.000705

GnomAD4 exome AF: 0.000381 AC: 552 AN: 1448820 Hom.: 5 Cov.: 31 AF XY: 0.000345 AC XY: 248 AN XY: 719538

African (AFR) AF: 0.0119 AC: 396 AN: 33182

American (AMR) AF: 0.000697 AC: 30 AN: 43072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25868

East Asian (EAS) AF: 0.00 AC: 0 AN: 39164

South Asian (SAS) AF: 0.000143 AC: 12 AN: 84194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51674

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5728

European-Non Finnish (NFE) AF: 0.00000904 AC: 10 AN: 1106012

Other (OTH) AF: 0.00165 AC: 99 AN: 59926

GnomAD4 genome AF: 0.00376 AC: 572 AN: 152192 Hom.: 4 Cov.: 29 AF XY: 0.00363 AC XY: 270 AN XY: 74396

African (AFR) AF: 0.0130 AC: 541 AN: 41486

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00281 Hom.: 4

Bravo AF: 0.00416

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Senior-Loken syndrome 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nephronophthisis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nephronophthisis 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.36
DANN	Benign	0.59
PhyloP100		-0.024
Mutation Taster		=100/0	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: rs113902159; hg19: chr1-6038319;