rs200046908

Variant names:

• chr3-132690511-T-C
• rs200046908
• NM_153240.5:c.2693+17A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153240.5(NPHP3):​c.2693+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,608,792 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: NPHP3 NM_153240.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.734
• 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-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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-132690511-T-C is Benign according to our data. Variant chr3-132690511-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00218 (332/152334) while in subpopulation SAS AF = 0.00394 (19/4820). AF 95% confidence interval is 0.00293. There are 1 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.2693+17A>G		intron	N/A	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.2699+17A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.2693+17A>G		intron	N/A	ENSP00000338766.5
	NPHP3	ENST00000465756.5	TSL:5	n.*601+17A>G		intron	N/A	ENSP00000419907.1
	NPHP3-ACAD11	ENST00000471702.2	TSL:2	n.*684+17A>G		intron	N/A	ENSP00000419763.1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00241 AC: 604 AN: 250818 AF XY: 0.00253

Gnomad AFR exome AF: 0.000686

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00330 AC: 4809 AN: 1456458 Hom.: 10 Cov.: 29 AF XY: 0.00331 AC XY: 2398 AN XY: 725054

African (AFR) AF: 0.000270 AC: 9 AN: 33366

American (AMR) AF: 0.00159 AC: 71 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00260 AC: 224 AN: 86130

European-Finnish (FIN) AF: 0.00303 AC: 162 AN: 53396

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.00372 AC: 4124 AN: 1107230

Other (OTH) AF: 0.00292 AC: 176 AN: 60192

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74484

African (AFR) AF: 0.000841 AC: 35 AN: 41596

American (AMR) AF: 0.00111 AC: 17 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4820

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00195

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.8
DANN	Benign	0.48
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism

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: rs200046908; hg19: chr3-132409355;