rs375051705

Variant names:

• chr1-5909165-G-C
• rs375051705
• NM_015102.5:c.1490C>G

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.1490C>G​(p.Pro497Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0025 in 1,601,166 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P497T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (122 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.56
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061025918).
• BP6: Variant 1-5909165-G-C is Benign according to our data. Variant chr1-5909165-G-C is described in ClinVar as Benign. ClinVar VariationId is 215518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00139 (212/152324) while in subpopulation SAS AF = 0.042 (203/4830). AF 95% confidence interval is 0.0373. There are 2 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1490C>G	p.Pro497Arg	missense	Exon 12 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.76-3382C>G		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.76-3385C>G		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.1490C>G	p.Pro497Arg	missense	Exon 12 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000489180.6	TSL:2	n.1490C>G		non_coding_transcript_exon	Exon 12 of 33	ENSP00000423747.1	O75161-2
	NPHP4	ENST00000378169.7	TSL:1	n.*516-3385C>G		intron	N/A	ENSP00000367411.3	D6RA06

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152206 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0426

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00527 AC: 1188 AN: 225450 AF XY: 0.00694

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000620

Gnomad ASJ exome AF: 0.000208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000533

Gnomad NFE exome AF: 0.0000588

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00261 AC: 3785 AN: 1448842 Hom.: 122 Cov.: 31 AF XY: 0.00374 AC XY: 2693 AN XY: 719118

African (AFR) AF: 0.000120 AC: 4 AN: 33294

American (AMR) AF: 0.0000699 AC: 3 AN: 42940

Ashkenazi Jewish (ASJ) AF: 0.000309 AC: 8 AN: 25860

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39262

South Asian (SAS) AF: 0.0429 AC: 3575 AN: 83248

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52476

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5752

European-Non Finnish (NFE) AF: 0.0000335 AC: 37 AN: 1106102

Other (OTH) AF: 0.00239 AC: 143 AN: 59908

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152324 Hom.: 2 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74494

African (AFR) AF: 0.000120 AC: 5 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0420 AC: 203 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00569 AC: 686

Asia WGS AF: 0.0160 AC: 57 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0061	T
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Uncertain	0.016	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.22		Gain of MoRF binding (P = 0.005)
MVP		0.93
MPC		0.39
ClinPred		0.038	T
GERP RS		3.5
Varity_R		0.085
gMVP		0.40
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs375051705; hg19: chr1-5969225;