2-110179672-T-A

Variant names:

• chr2-110179672-T-A
• rs759699517
• NM_001128178.3:c.156A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001128178.3(NPHP1):​c.156A>T​(p.Leu52Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000839 in 1,192,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L52L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38161784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP1	NM_001128178.3	c.156A>T	p.Leu52Phe	missense_variant	Exon 3 of 20	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7	c.156A>T	p.Leu52Phe	missense_variant	Exon 3 of 20	1	NM_001128178.3	ENSP00000389879.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.39e-7 AC: 1 AN: 1192448 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 604614

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28248

American (AMR) AF: 0.00 AC: 0 AN: 43550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23922

East Asian (EAS) AF: 0.00 AC: 0 AN: 38130

South Asian (SAS) AF: 0.00 AC: 0 AN: 80370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 0.00000115 AC: 1 AN: 873242

Other (OTH) AF: 0.00 AC: 0 AN: 51012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;.;T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T;T;T;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.
PhyloP100		1.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N;N;N;N;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.025	D;D;D;D;D
Sift4G	Benign	0.089	T;T;T;T;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.28
MutPred		0.34		Gain of methylation at K53 (P = 0.0413);Gain of methylation at K53 (P = 0.0413);Gain of methylation at K53 (P = 0.0413);Gain of methylation at K53 (P = 0.0413);Gain of methylation at K53 (P = 0.0413);
MVP		0.91
MPC		0.46
ClinPred		0.95	D
GERP RS		-0.13
Varity_R		0.14
gMVP		0.28
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs759699517; hg19: chr2-110937249;