rs116606479

Variant names:

• chr1-5874953-C-T
• rs116606479
• NM_015102.5:c.2965G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

The NM_015102.5(NPHP4):​c.2965G>A​(p.Glu989Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,613,458 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: 5.87
• Publications: 5 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36386117).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000617 (94/152240) while in subpopulation AFR AF = 0.00168 (70/41548). AF 95% confidence interval is 0.00137. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2965G>A	p.Glu989Lys	missense	Exon 21 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.1429G>A	p.Glu477Lys	missense	Exon 17 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1426G>A	p.Glu476Lys	missense	Exon 18 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.2965G>A	p.Glu989Lys	missense	Exon 21 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*1866G>A		non_coding_transcript_exon	Exon 18 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.*776G>A		non_coding_transcript_exon	Exon 24 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000430 AC: 107 AN: 248728 AF XY: 0.000415

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000261 AC: 381 AN: 1461218 Hom.: 1 Cov.: 33 AF XY: 0.000275 AC XY: 200 AN XY: 726884

African (AFR) AF: 0.00194 AC: 65 AN: 33476

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52928

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000162 AC: 180 AN: 1111860

Other (OTH) AF: 0.000480 AC: 29 AN: 60370

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74446

African (AFR) AF: 0.00168 AC: 70 AN: 41548

American (AMR) AF: 0.000523 AC: 8 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68006

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000831

ESP6500AA AF: 0.00162 AC: 7

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	1	1	Nephronophthisis (2)
-	2	-	Nephronophthisis 4 (2)
-	1	-	Focal segmental glomerulosclerosis;C1846979:Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 (1)
-	1	-	NPHP4-related disorder (1)
-	1	-	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.95
MPC		0.41
ClinPred		0.036	T
GERP RS		5.0
Varity_R		0.40
gMVP		0.96
Mutation Taster		=63/37	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: rs116606479; hg19: chr1-5935013;