3-132721994-G-C

Position:

• chr3-132721994-G-C

Variant summary

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

The NM_153240.5(NPHP3):​c.362C>G​(p.Thr121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72

Genes affected

NPHP3 (HGNC:7907): (nephrocystin 3) This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]

NPHP3-AS1 (HGNC:):

NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

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=0.18125227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.362C>G	p.Thr121Arg	missense_variant	1/27	ENST00000337331.10	NP_694972.3
NPHP3-AS1	NR_002811.2	n.245G>C		non_coding_transcript_exon_variant	1/11
NPHP3-ACAD11	NR_037804.1	n.466C>G		non_coding_transcript_exon_variant	1/45
NPHP3-AS1	NR_152743.1	n.245G>C		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.362C>G	p.Thr121Arg	missense_variant	1/27	1	NM_153240.5	ENSP00000338766.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460856 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NPHP3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with arginine at codon 121 of the NPHP3 protein (p.Thr121Arg). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Benign	0.84
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.37	N;N
REVEL	Uncertain	0.50
Sift	Benign	0.35	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0020	B;.
Vest4		0.26
MutPred		0.48		Loss of ubiquitination at K118 (P = 0.0184);Loss of ubiquitination at K118 (P = 0.0184);
MVP		0.75
MPC		0.21
ClinPred		0.23	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs1940240950; hg19: chr3-132440838;