rs33958626

Variant names:

• chr2-110201449-G-A
• rs33958626
• NM_001128178.3:c.115C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-110201449-G-A
• chr2-110201449-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001128178.3(NPHP1):​c.115C>T​(p.Pro39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,324 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. P39T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037632585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP1	NM_001128178.3	c.115C>T	p.Pro39Ser	missense_variant	Exon 2 of 20	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7	c.115C>T	p.Pro39Ser	missense_variant	Exon 2 of 20	1	NM_001128178.3	ENSP00000389879.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457324 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725072

African (AFR) AF: 0.0000299 AC: 1 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109056

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.048	.;.;T;.;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.69	T;T;T;T;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.038	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L;L;L;L;.;.
PhyloP100		-0.11
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.54	N;N;N;N;N;D
REVEL	Benign	0.025
Sift	Benign	0.35	T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T
Polyphen		0.0040	B;B;B;B;B;B
Vest4		0.20
MutPred		0.24		Gain of MoRF binding (P = 0.0457);Gain of MoRF binding (P = 0.0457);Gain of MoRF binding (P = 0.0457);Gain of MoRF binding (P = 0.0457);Gain of MoRF binding (P = 0.0457);Gain of MoRF binding (P = 0.0457);
MVP		0.63
MPC		0.082
ClinPred		0.055	T
GERP RS		0.48
PromoterAI		-0.00010	Neutral
Varity_R		0.030
gMVP		0.092
Mutation Taster		=92/8	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: rs33958626; hg19: chr2-110959026;