rs1553775714

chr3-132722063-T-Achr3-132722063-T-C

Variant summary

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

The NM_153240.5(NPHP3):c.293A>T(p.Tyr98Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y98C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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:24129): (NPHP3 antisense RNA 1)

NPHP3-ACAD11 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP3	NM_153240.5	c.293A>T	p.Tyr98Phe	missense_variant	1/27	ENST00000337331.10
NPHP3-AS1	NR_002811.2	n.314T>A		non_coding_transcript_exon_variant	1/11
NPHP3-ACAD11	NR_037804.1	n.397A>T		non_coding_transcript_exon_variant	1/45
NPHP3-AS1	NR_152743.1	n.314T>A		non_coding_transcript_exon_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP3	ENST00000337331.10	c.293A>T	p.Tyr98Phe	missense_variant	1/27	1	NM_153240.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Invitae

Jun 27, 2020

This sequence change replaces tyrosine with phenylalanine at codon 98 of the NPHP3 protein (p.Tyr98Phe). The tyrosine residue is moderately conserved and there is a small physicochemical difference between tyrosine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NPHP3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.30	N;D
REVEL	Uncertain	0.41
Sift	Benign	0.32	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.82	P;.
Vest4		0.62
MutPred		0.59		Gain of glycosylation at Y98 (P = 0.0606);Gain of glycosylation at Y98 (P = 0.0606);
MVP		0.79
MPC		0.23
ClinPred		0.93	D
GERP RS		2.4
Varity_R		0.17
gMVP		0.23

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: rs1553775714; hg19: chr3-132440907;