rs147932449

Variant names:

• chr3-132715178-A-T
• rs147932449
• NM_153240.5:c.864T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153240.5(NPHP3):​c.864T>A​(p.Thr288Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,611,492 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (73 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (69 hom.)
• Consequence: NPHP3 NM_153240.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.251
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-132715178-A-T is Benign according to our data. Variant chr3-132715178-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.251 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

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.864T>A	p.Thr288Thr	synonymous	Exon 5 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.968T>A		non_coding_transcript_exon	Exon 5 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.864T>A	p.Thr288Thr	synonymous	Exon 5 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000971413.1		c.864T>A	p.Thr288Thr	synonymous	Exon 5 of 25	ENSP00000641472.1
	NPHP3	ENST00000971412.1		c.864T>A	p.Thr288Thr	synonymous	Exon 5 of 23	ENSP00000641471.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2520 AN: 152216 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00436 AC: 1095 AN: 251296 AF XY: 0.00324

Gnomad AFR exome AF: 0.0596

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00181 AC: 2642 AN: 1459158 Hom.: 69 Cov.: 28 AF XY: 0.00163 AC XY: 1186 AN XY: 726118

African (AFR) AF: 0.0631 AC: 2107 AN: 33398

American (AMR) AF: 0.00253 AC: 113 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 91 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5754

European-Non Finnish (NFE) AF: 0.0000406 AC: 45 AN: 1109694

Other (OTH) AF: 0.00444 AC: 268 AN: 60298

GnomAD4 genome AF: 0.0167 AC: 2546 AN: 152334 Hom.: 73 Cov.: 33 AF XY: 0.0164 AC XY: 1220 AN XY: 74492

African (AFR) AF: 0.0580 AC: 2412 AN: 41566

American (AMR) AF: 0.00555 AC: 85 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68030

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00511 Hom.: 5

Bravo AF: 0.0193

Asia WGS AF: 0.00405 AC: 14 AN: 3474

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.2
DANN	Benign	0.66
PhyloP100		-0.25
Mutation Taster		=82/18	polymorphism (auto)

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: rs147932449; hg19: chr3-132434022;