NM_015102.5:c.3876C>T

Variant names:

• chr1-5864458-G-A
• rs115526767
• NM_015102.5:c.3876C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015102.5(NPHP4):​c.3876C>T​(p.Gly1292Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,605,318 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (14 hom., cov: 33)
  • Exomes 𝑓: 0.016 (219 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.52
• Publications: 4 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=-0.83).
• BP6: Variant 1-5864458-G-A is Benign according to our data. Variant chr1-5864458-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0096 (1463/152322) while in subpopulation NFE AF = 0.0161 (1095/68020). AF 95% confidence interval is 0.0153. There are 14 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.3876C>T	p.Gly1292Gly	synonymous	Exon 28 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.2340C>T	p.Gly780Gly	synonymous	Exon 24 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.2337C>T	p.Gly779Gly	synonymous	Exon 25 of 27	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3876C>T	p.Gly1292Gly	synonymous	Exon 28 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*2777C>T		non_coding_transcript_exon	Exon 25 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000460696.1	TSL:1	n.2624C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1463 AN: 152204 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00930 AC: 2132 AN: 229252 AF XY: 0.00941

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.00447

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00572

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.00953

GnomAD4 exome AF: 0.0156 AC: 22728 AN: 1452996 Hom.: 219 Cov.: 32 AF XY: 0.0152 AC XY: 10940 AN XY: 721954

African (AFR) AF: 0.00258 AC: 86 AN: 33312

American (AMR) AF: 0.00455 AC: 198 AN: 43484

Ashkenazi Jewish (ASJ) AF: 0.00220 AC: 57 AN: 25904

East Asian (EAS) AF: 0.0000764 AC: 3 AN: 39292

South Asian (SAS) AF: 0.00395 AC: 335 AN: 84772

European-Finnish (FIN) AF: 0.00700 AC: 365 AN: 52152

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5746

European-Non Finnish (NFE) AF: 0.0187 AC: 20770 AN: 1108294

Other (OTH) AF: 0.0149 AC: 894 AN: 60040

GnomAD4 genome AF: 0.00960 AC: 1463 AN: 152322 Hom.: 14 Cov.: 33 AF XY: 0.00906 AC XY: 675 AN XY: 74484

African (AFR) AF: 0.00298 AC: 124 AN: 41582

American (AMR) AF: 0.00816 AC: 125 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0161 AC: 1095 AN: 68020

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0125 Hom.: 12

Bravo AF: 0.00969

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.51
DANN	Benign	0.83
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115526767; hg19: chr1-5924518; COSMIC: COSV105928980; COSMIC: COSV105928980;