chr3-132721986-T-C

Variant names:

• chr3-132721986-T-C
• rs1553775689
• NM_153240.5:c.370A>G

Variant summary

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

The NM_153240.5(NPHP3):​c.370A>G​(p.Lys124Glu) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

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: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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.370A>G	p.Lys124Glu	missense_variant	Exon 1 of 27	ENST00000337331.10	NP_694972.3
NPHP3-AS1	NR_002811.2	n.237T>C		non_coding_transcript_exon_variant	Exon 1 of 11
NPHP3-ACAD11	NR_037804.1	n.474A>G		non_coding_transcript_exon_variant	Exon 1 of 45
NPHP3-AS1	NR_152743.1	n.237T>C		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.370A>G	p.Lys124Glu	missense_variant	Exon 1 of 27	1	NM_153240.5	ENSP00000338766.5

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

not provided Uncertain:1

Jan 18, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.79	N;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	D;.
Vest4		0.65
MutPred		0.30		Loss of MoRF binding (P = 0.001);Loss of MoRF binding (P = 0.001);
MVP		0.91
MPC		0.47
ClinPred		0.94	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.47

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: rs1553775689; hg19: chr3-132440830;