rs398124547

chr3-132687229-TA-Tchr3-132687229-TA-TAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_153240.5(NPHP3):c.3126-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000734 in 1,216,238 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: NPHP3 NM_153240.5 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.265

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 3-132687229-TA-T is Benign according to our data. Variant chr3-132687229-TA-T is described in ClinVar as [Benign]. Clinvar id is 96515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132687229-TA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00066 (100/151480) while in subpopulation AMR AF= 0.00558 (85/15226). AF 95% confidence interval is 0.00463. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP3	NM_153240.5	c.3126-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000337331.10
NPHP3-ACAD11	NR_037804.1	n.3132-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP3	ENST00000337331.10	c.3126-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_153240.5	P1

Frequencies

GnomAD3 genomes AF: 0.000661 AC: 100 AN: 151366 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00559

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.00198 AC: 434 AN: 219134 Hom.: 1 AF XY: 0.00144 AC XY: 172 AN XY: 119050

Gnomad AFR exome AF: 0.000410

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000256

Gnomad FIN exome AF: 0.000241

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.000741

GnomAD4 exome AF: 0.000745 AC: 793 AN: 1064758 Hom.: 2 Cov.: 16 AF XY: 0.000615 AC XY: 336 AN XY: 545916

Gnomad4 AFR exome AF: 0.000427

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0000430

Gnomad4 EAS exome AF: 0.0000268

Gnomad4 SAS exome AF: 0.000156

Gnomad4 FIN exome AF: 0.000190

Gnomad4 NFE exome AF: 0.000317

Gnomad4 OTH exome AF: 0.000747

GnomAD4 genome AF: 0.000660 AC: 100 AN: 151480 Hom.: 0 Cov.: 33 AF XY: 0.000770 AC XY: 57 AN XY: 74024

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00558

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.000869 Hom.: 0

Bravo AF: 0.00144

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 22, 2015

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs398124547; hg19: chr3-132406073;