NM_153240.5:c.2089-9C>T

Variant names:

• chr3-132696822-G-A
• rs141397228
• NM_153240.5:c.2089-9C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_153240.5(NPHP3):​c.2089-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,611,492 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (20 hom.)
• Consequence: NPHP3 NM_153240.5 intron
• Scores: Splicing: ADA: 0.6957
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.80
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 3-132696822-G-A is Benign according to our data. Variant chr3-132696822-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211684.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00384 (585/152284) while in subpopulation NFE AF = 0.0052 (354/68014). AF 95% confidence interval is 0.00476. There are 2 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.2089-9C>T		intron	N/A	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.2095-9C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.2089-9C>T		intron	N/A	ENSP00000338766.5
	NPHP3	ENST00000465756.5	TSL:5	n.*79+438C>T		intron	N/A	ENSP00000419907.1
	NPHP3-ACAD11	ENST00000471702.2	TSL:2	n.*80-9C>T		intron	N/A	ENSP00000419763.1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152166 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00427 AC: 1071 AN: 251100 AF XY: 0.00423

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00462 AC: 6745 AN: 1459208 Hom.: 20 Cov.: 30 AF XY: 0.00449 AC XY: 3260 AN XY: 726154

African (AFR) AF: 0.000419 AC: 14 AN: 33424

American (AMR) AF: 0.000425 AC: 19 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86208

European-Finnish (FIN) AF: 0.0156 AC: 832 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00514 AC: 5701 AN: 1109954

Other (OTH) AF: 0.00294 AC: 177 AN: 60306

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74480

African (AFR) AF: 0.000987 AC: 41 AN: 41554

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00520 AC: 354 AN: 68014

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00417 Hom.: 3

Bravo AF: 0.00259

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 3 (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	-0.25
CADD	Benign	22
DANN	Benign	0.75
PhyloP100		2.8
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.70
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.010		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: rs141397228; hg19: chr3-132415666;