chr1-5880183-G-A

Variant names:

• chr1-5880183-G-A
• rs17472401
• NM_015102.5:c.2542C>T

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.2542C>T​(p.Arg848Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,613,640 control chromosomes in the GnomAD database, including 435 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. R848Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 33)
  • Exomes 𝑓: 0.022 (410 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: 1.48
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007936746).
• BP6: Variant 1-5880183-G-A is Benign according to our data. Variant chr1-5880183-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95675.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 = 0.0156 (2378/152308) while in subpopulation NFE AF = 0.0237 (1614/68022). AF 95% confidence interval is 0.0228. There are 25 homozygotes in GnomAd4. There are 1132 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.2542C>T	p.Arg848Trp	missense	Exon 19 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.1006C>T	p.Arg336Trp	missense	Exon 15 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1003C>T	p.Arg335Trp	missense	Exon 16 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.2542C>T	p.Arg848Trp	missense	Exon 19 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*1443C>T		non_coding_transcript_exon	Exon 16 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.2539C>T		non_coding_transcript_exon	Exon 19 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2378 AN: 152190 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0155 AC: 3841 AN: 248334 AF XY: 0.0157

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.00418

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000502

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0216 AC: 31535 AN: 1461332 Hom.: 410 Cov.: 32 AF XY: 0.0213 AC XY: 15449 AN XY: 726898

African (AFR) AF: 0.00358 AC: 120 AN: 33476

American (AMR) AF: 0.00466 AC: 208 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 738 AN: 26130

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39690

South Asian (SAS) AF: 0.00505 AC: 435 AN: 86170

European-Finnish (FIN) AF: 0.0248 AC: 1326 AN: 53378

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.0247 AC: 27458 AN: 1111690

Other (OTH) AF: 0.0195 AC: 1178 AN: 60360

GnomAD4 genome AF: 0.0156 AC: 2378 AN: 152308 Hom.: 25 Cov.: 33 AF XY: 0.0152 AC XY: 1132 AN XY: 74474

African (AFR) AF: 0.00435 AC: 181 AN: 41566

American (AMR) AF: 0.00803 AC: 123 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.00455 AC: 22 AN: 4830

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0237 AC: 1614 AN: 68022

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0203 Hom.: 156

Bravo AF: 0.0140

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00363 AC: 15

ESP6500EA AF: 0.0219 AC: 184

ExAC AF: 0.0147 AC: 1785

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0215

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	3	Nephronophthisis 4 (4)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.030
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0079	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.58
MPC		0.40
ClinPred		0.015	T
GERP RS		0.78
Varity_R		0.11
gMVP		0.47
Mutation Taster		=90/10	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: rs17472401; hg19: chr1-5940243;