rs149887461

Variant names:

• chr2-110143602-C-T
• rs149887461
• NM_001128178.3:c.1469G>A

Variant summary

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

The NM_001128178.3(NPHP1):​c.1469G>A​(p.Arg490Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,754 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R490S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (7 hom.)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 1.99
• Publications: 6 publications found

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 Gene-Disease associations (from GenCC):

• Joubert syndrome with renal defect

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• nephronophthisis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome

  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=0.006969422).
• BP6: Variant 2-110143602-C-T is Benign according to our data. Variant chr2-110143602-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 330730.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00044 (67/152248) while in subpopulation SAS AF = 0.00332 (16/4820). AF 95% confidence interval is 0.00208. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128178.3. 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
	NPHP1	NM_001128178.3	MANE Select	c.1469G>A	p.Arg490Lys	missense	Exon 16 of 20	NP_001121650.1	O15259-2
	NPHP1	NM_000272.5		c.1637G>A	p.Arg546Lys	missense	Exon 16 of 20	NP_000263.2
	NPHP1	NM_207181.4		c.1634G>A	p.Arg545Lys	missense	Exon 16 of 20	NP_997064.2	O15259-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.1469G>A	p.Arg490Lys	missense	Exon 16 of 20	ENSP00000389879.3	O15259-2
	NPHP1	ENST00000316534.8	TSL:1	c.1637G>A	p.Arg546Lys	missense	Exon 16 of 20	ENSP00000313169.4	O15259-4
	NPHP1	ENST00000393272.7	TSL:1	c.1634G>A	p.Arg545Lys	missense	Exon 16 of 20	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000624 AC: 157 AN: 251414 AF XY: 0.000751

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000310 AC: 453 AN: 1461506 Hom.: 7 Cov.: 30 AF XY: 0.000397 AC XY: 289 AN XY: 727090

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000559 AC: 25 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00231 AC: 199 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000140 AC: 156 AN: 1111694

Other (OTH) AF: 0.000580 AC: 35 AN: 60382

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74440

African (AFR) AF: 0.0000481 AC: 2 AN: 41550

American (AMR) AF: 0.00196 AC: 30 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000350 Hom.: 2

Bravo AF: 0.000623

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000618 AC: 75

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	-	Joubert syndrome with renal defect (1)
-	-	1	Nephronophthisis (1)
-	1	-	Nephronophthisis 1 (1)
-	-	1	not provided (1)
-	-	1	NPHP1-related disorder (1)
-	1	-	Senior-Loken syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		2.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.069
Sift	Benign	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.15	B
Vest4		0.094
MVP		0.67
MPC		0.20
ClinPred		0.014	T
GERP RS		4.3
Varity_R		0.055
gMVP		0.45
Mutation Taster		=100/0	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: rs149887461; hg19: chr2-110901179;