chr3-132719800-G-A

Variant names:

• chr3-132719800-G-A
• rs771742823
• NM_153240.5:c.424C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153240.5(NPHP3):​c.424C>T​(p.Arg142*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,596,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: NPHP3 NM_153240.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.15
• Publications: 3 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-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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-132719800-G-A is Pathogenic according to our data. Variant chr3-132719800-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 430726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.424C>T	p.Arg142*	stop_gained	Exon 2 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.528C>T		non_coding_transcript_exon	Exon 2 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.424C>T	p.Arg142*	stop_gained	Exon 2 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000971413.1		c.424C>T	p.Arg142*	stop_gained	Exon 2 of 25	ENSP00000641472.1
	NPHP3	ENST00000971412.1		c.424C>T	p.Arg142*	stop_gained	Exon 2 of 23	ENSP00000641471.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151448 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249016 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444962 Hom.: 0 Cov.: 28 AF XY: 0.00000417 AC XY: 3 AN XY: 718848

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 83668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101522

Other (OTH) AF: 0.00 AC: 0 AN: 59524

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151448 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73912

African (AFR) AF: 0.00 AC: 0 AN: 41214

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.0000464 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Nephronophthisis 3 (2)
1	-	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		3.2
Vest4		0.93
GERP RS		5.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771742823; hg19: chr3-132438644; COSMIC: COSV58129232; COSMIC: COSV58129232;