chr3-132681258-CTT-C

Position:

• chr3-132681258-CTT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_153240.5(NPHP3):​c.*650_*651del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0889 in 105,186 control chromosomes in the GnomAD database, including 200 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.089 (200 hom., cov: 23)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: NPHP3 NM_153240.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.19

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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.*650_*651del		3_prime_UTR_variant	27/27	ENST00000337331.10	NP_694972.3
NPHP3-ACAD11	NR_037804.1	n.3995+654_3995+655del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.*650_*651del		3_prime_UTR_variant	27/27	1	NM_153240.5	ENSP00000338766	P1
NPHP3	ENST00000474871.5	n.3842_3843del		non_coding_transcript_exon_variant	11/11	2
NPHP3	ENST00000493732.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0890 AC: 9350 AN: 105104 Hom.: 200 Cov.: 23

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.0519

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.108

GnomAD4 exome AF: 0.0270 AC: 2 AN: 74 Hom.: 0 AF XY: 0.0370 AC XY: 2 AN XY: 54

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.0889 AC: 9348 AN: 105112 Hom.: 200 Cov.: 23 AF XY: 0.0897 AC XY: 4386 AN XY: 48914

Gnomad4 AFR AF: 0.0267

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.0995

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Renal-hepatic-pancreatic dysplasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Meckel-Gruber syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886058000; hg19: chr3-132400102;