NM_015102.5:c.2882G>A

Variant names:

• chr1-5875036-C-T
• rs183885357
• NM_015102.5:c.2882G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015102.5(NPHP4):​c.2882G>A​(p.Arg961His) variant causes a missense change. The variant allele was found at a frequency of 0.00336 in 1,609,654 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R961C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (14 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 3.64
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016577065).
• BP6: Variant 1-5875036-C-T is Benign according to our data. Variant chr1-5875036-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167373.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00194 (296/152328) while in subpopulation NFE AF = 0.00307 (209/68028). AF 95% confidence interval is 0.00273. There are 0 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.2882G>A	p.Arg961His	missense	Exon 21 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.1346G>A	p.Arg449His	missense	Exon 17 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1343G>A	p.Arg448His	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.2882G>A	p.Arg961His	missense	Exon 21 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*1783G>A		non_coding_transcript_exon	Exon 18 of 27	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.*693G>A		non_coding_transcript_exon	Exon 24 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 296 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00244 AC: 598 AN: 244952 AF XY: 0.00245

Gnomad AFR exome AF: 0.000515

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00349

Gnomad NFE exome AF: 0.00376

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00351 AC: 5119 AN: 1457326 Hom.: 14 Cov.: 33 AF XY: 0.00341 AC XY: 2473 AN XY: 725100

African (AFR) AF: 0.000568 AC: 19 AN: 33478

American (AMR) AF: 0.00201 AC: 90 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86234

European-Finnish (FIN) AF: 0.00230 AC: 113 AN: 49176

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00415 AC: 4614 AN: 1111804

Other (OTH) AF: 0.00336 AC: 203 AN: 60352

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74484

African (AFR) AF: 0.000722 AC: 30 AN: 41568

American (AMR) AF: 0.00189 AC: 29 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00236 Hom.: 0

Bravo AF: 0.00238

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00409 AC: 35

ExAC AF: 0.00229 AC: 278

EpiCase AF: 0.00458

EpiControl AF: 0.00356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.65
Sift	Benign	0.052	T
Sift4G	Benign	0.076	T
Polyphen		0.98	D
Vest4		0.35
MVP		0.94
MPC		0.12
ClinPred		0.025	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.61
Mutation Taster		=85/15	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: rs183885357; hg19: chr1-5935096; COSMIC: COSV65395561; COSMIC: COSV65395561;