rs12116997

Variant names:

• chr1-5909185-G-A
• rs12116997
• NM_015102.5:c.1470C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015102.5(NPHP4):​c.1470C>T​(p.Leu490Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,603,376 control chromosomes in the GnomAD database, including 989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (226 hom., cov: 33)
  • Exomes 𝑓: 0.027 (763 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.09
• Publications: 7 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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-5909185-G-A is Benign according to our data. Variant chr1-5909185-G-A is described in ClinVar as Benign. ClinVar VariationId is 260543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.1470C>T	p.Leu490Leu	synonymous	Exon 12 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.76-3402C>T		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.76-3405C>T		intron	N/A	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.1470C>T	p.Leu490Leu	synonymous	Exon 12 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000489180.6	TSL:2	n.1470C>T		non_coding_transcript_exon	Exon 12 of 33	ENSP00000423747.1	O75161-2
	NPHP4	ENST00000378169.7	TSL:1	n.*516-3405C>T		intron	N/A	ENSP00000367411.3	D6RA06

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6971 AN: 152048 Hom.: 226 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0249

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0292 AC: 6689 AN: 229090 AF XY: 0.0284

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0274 AC: 39767 AN: 1451210 Hom.: 763 Cov.: 32 AF XY: 0.0271 AC XY: 19544 AN XY: 720546

African (AFR) AF: 0.107 AC: 3580 AN: 33322

American (AMR) AF: 0.0123 AC: 532 AN: 43320

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 859 AN: 25910

East Asian (EAS) AF: 0.0000762 AC: 3 AN: 39386

South Asian (SAS) AF: 0.0320 AC: 2678 AN: 83618

European-Finnish (FIN) AF: 0.0420 AC: 2211 AN: 52596

Middle Eastern (MID) AF: 0.0360 AC: 207 AN: 5752

European-Non Finnish (NFE) AF: 0.0252 AC: 27919 AN: 1107310

Other (OTH) AF: 0.0296 AC: 1778 AN: 59996

GnomAD4 genome AF: 0.0458 AC: 6971 AN: 152166 Hom.: 226 Cov.: 33 AF XY: 0.0455 AC XY: 3385 AN XY: 74400

African (AFR) AF: 0.101 AC: 4185 AN: 41490

American (AMR) AF: 0.0167 AC: 255 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5162

South Asian (SAS) AF: 0.0259 AC: 125 AN: 4826

European-Finnish (FIN) AF: 0.0406 AC: 431 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0249 AC: 1695 AN: 67984

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0326 Hom.: 224

Bravo AF: 0.0466

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Nephronophthisis 4 (2)
-	-	2	not provided (2)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.48
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs12116997; hg19: chr1-5969245; COSMIC: COSV65394924; COSMIC: COSV65394924;