rs145479679

Positions:

• chr2-110201431-T-C
• chr2-110201431-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128178.3(NPHP1):​c.133A>G​(p.Ile45Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11955792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP1	NM_001128178.3	c.133A>G	p.Ile45Val	missense_variant	2/20	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7	c.133A>G	p.Ile45Val	missense_variant	2/20	1	NM_001128178.3	ENSP00000389879.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247566 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452722 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 722946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.088	.;.;T;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.69	T;T;T;T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L;L;L;L;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.33	N;N;N;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.22	T;T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T;T
Polyphen		0.0040	B;B;B;B;B;B
Vest4		0.25
MutPred		0.24		Gain of MoRF binding (P = 0.108);Gain of MoRF binding (P = 0.108);Gain of MoRF binding (P = 0.108);Gain of MoRF binding (P = 0.108);Gain of MoRF binding (P = 0.108);Gain of MoRF binding (P = 0.108);
MVP		0.81
MPC		0.077
ClinPred		0.087	T
GERP RS		2.9
Varity_R		0.039
gMVP		0.055

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

Publications

LitVar

Other links and lift over

dbSNP: rs145479679; hg19: chr2-110959008;