rs1940240950

Variant names:

• chr3-132721994-G-C
• rs1940240950
• NM_153240.5:c.362C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-132721994-G-C
• chr3-132721994-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T121P) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18125227).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153240.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.362C>G	p.Thr121Arg	missense	Exon 1 of 27	NP_694972.3
	NPHP3-AS1	NR_002811.2		n.245G>C		non_coding_transcript_exon	Exon 1 of 11
	NPHP3-ACAD11	NR_037804.1		n.466C>G		non_coding_transcript_exon	Exon 1 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.362C>G	p.Thr121Arg	missense	Exon 1 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000383282.3	TSL:1	c.362C>G	p.Thr121Arg	missense	Exon 1 of 2	ENSP00000372769.2	Q7Z494-7
	NPHP3-AS1	ENST00000489343.5	TSL:1	n.245G>C		non_coding_transcript_exon	Exon 1 of 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

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.50
Sift	Benign	0.35	T
Sift4G	Benign	0.57	T
Polyphen		0.0020	B
Vest4		0.26
MutPred		0.48		Loss of ubiquitination at K118 (P = 0.0184)
MVP		0.75
MPC		0.21
ClinPred		0.23	T
GERP RS		2.6
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.34
Mutation Taster		=10/90	disease causing

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: rs1940240950; hg19: chr3-132440838;