NM_153240.5:c.2571-7T>C

Variant names:

• chr3-132690657-A-G
• rs62292468
• NM_153240.5:c.2571-7T>C

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.2571-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,613,306 control chromosomes in the GnomAD database, including 1,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1405 hom.)
• Consequence: NPHP3 NM_153240.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001937
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.191
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 3-132690657-A-G is Benign according to our data. Variant chr3-132690657-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0288 (4392/152290) while in subpopulation NFE AF = 0.0475 (3232/68002). AF 95% confidence interval is 0.0462. There are 102 homozygotes in GnomAd4. There are 2022 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 102 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.2571-7T>C		splice_region intron	N/A	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.2577-7T>C		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.2571-7T>C		splice_region intron	N/A	ENSP00000338766.5
	NPHP3	ENST00000465756.5	TSL:5	n.*479-7T>C		splice_region intron	N/A	ENSP00000419907.1
	NPHP3-ACAD11	ENST00000471702.2	TSL:2	n.*562-7T>C		splice_region intron	N/A	ENSP00000419763.1

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4397 AN: 152172 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0475

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0304 AC: 7637 AN: 251272 AF XY: 0.0308

Gnomad AFR exome AF: 0.00715

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0494

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0406 AC: 59340 AN: 1461016 Hom.: 1405 Cov.: 31 AF XY: 0.0397 AC XY: 28871 AN XY: 726884

African (AFR) AF: 0.00663 AC: 222 AN: 33460

American (AMR) AF: 0.0108 AC: 484 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0387 AC: 1012 AN: 26118

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39666

South Asian (SAS) AF: 0.0110 AC: 948 AN: 86230

European-Finnish (FIN) AF: 0.0308 AC: 1645 AN: 53414

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5764

European-Non Finnish (NFE) AF: 0.0475 AC: 52832 AN: 1111274

Other (OTH) AF: 0.0344 AC: 2075 AN: 60370

GnomAD4 genome AF: 0.0288 AC: 4392 AN: 152290 Hom.: 102 Cov.: 32 AF XY: 0.0272 AC XY: 2022 AN XY: 74460

African (AFR) AF: 0.00784 AC: 326 AN: 41578

American (AMR) AF: 0.0166 AC: 254 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3468

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

South Asian (SAS) AF: 0.00952 AC: 46 AN: 4830

European-Finnish (FIN) AF: 0.0297 AC: 315 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0475 AC: 3232 AN: 68002

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.0410 Hom.: 69

Bravo AF: 0.0280

Asia WGS AF: 0.00520 AC: 18 AN: 3476

EpiCase AF: 0.0481

EpiControl AF: 0.0487

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 3 (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	-0.94
CADD	Benign	0.51
DANN	Benign	0.35
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs62292468; hg19: chr3-132409501;