chr2-110201431-T-C

Variant names:

• chr2-110201431-T-C
• rs145479679
• NM_001128178.3:c.133A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I45L) has been classified as Likely benign.

• 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
• Publications: 4 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	NM_001128178.3	MANE Select	c.133A>G	p.Ile45Val	missense	Exon 2 of 20	NP_001121650.1
	NPHP1	NM_000272.5		c.133A>G	p.Ile45Val	missense	Exon 2 of 20	NP_000263.2
	NPHP1	NM_207181.4		c.133A>G	p.Ile45Val	missense	Exon 2 of 20	NP_997064.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.133A>G	p.Ile45Val	missense	Exon 2 of 20	ENSP00000389879.3
	NPHP1	ENST00000316534.8	TSL:1	c.133A>G	p.Ile45Val	missense	Exon 2 of 20	ENSP00000313169.4
	NPHP1	ENST00000393272.7	TSL:1	c.133A>G	p.Ile45Val	missense	Exon 2 of 20	ENSP00000376953.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000808 AC: 2 AN: 247566 AF XY: 0.00000747

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.0000449 AC: 2 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105228

Other (OTH) AF: 0.00 AC: 0 AN: 60082

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.37
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.027
Sift	Benign	0.22	T
Sift4G	Benign	0.46	T
Polyphen		0.0040	B
Vest4		0.25
MutPred		0.24		Gain of MoRF binding (P = 0.108)
MVP		0.81
MPC		0.077
ClinPred		0.087	T
GERP RS		2.9
PromoterAI		0.0088	Neutral
Varity_R		0.039
gMVP		0.055
Mutation Taster		=94/6	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: rs145479679; hg19: chr2-110959008;