rs528302390

Positions:

• chr7-47831213-TCA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138295.5(PKD1L1):​c.6473+2_6473+3delTG variant causes a splice donor, splice region, intron change. The variant allele was found at a frequency of 0.000861 in 1,611,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (0 hom.)
• Consequence: PKD1L1 NM_138295.5 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.86

Genes affected

PKD1L1 (HGNC:18053): (polycystin 1 like 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family containing 11 transmembrane domains, a receptor for egg jelly (REJ) domain, and a polycystin-1, lipoxygenase, alpha-toxin (PLAT) domain. The encoded protein may play a role in the male reproductive system. Alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-47831213-TCA-T is Pathogenic according to our data. Variant chr7-47831213-TCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 235796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1L1	NM_138295.5	c.6473+2_6473+3delTG		splice_donor_variant, splice_region_variant, intron_variant		ENST00000289672.7	NP_612152.1
PKD1L1	XM_017011798.3	c.6650+2_6650+3delTG		splice_donor_variant, splice_region_variant, intron_variant			XP_016867287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1L1	ENST00000289672.7	c.6473+2_6473+3delTG		splice_donor_variant, splice_region_variant, intron_variant		1	NM_138295.5	ENSP00000289672.2
PKD1L1	ENST00000690269.1	c.6473+2_6473+3delTG		splice_donor_variant, splice_region_variant, intron_variant				ENSP00000510743.1
PKD1L1	ENST00000685709.1	c.6305+2_6305+3delTG		splice_donor_variant, splice_region_variant, intron_variant				ENSP00000509540.1
PKD1L1	ENST00000686775.1	c.375+3124_375+3125delTG		intron_variant				ENSP00000508550.1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

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: 0.000955

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000366 AC: 91 AN: 248798 Hom.: 0 AF XY: 0.000379 AC XY: 51 AN XY: 134576

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.000407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000718

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000899 AC: 1311 AN: 1459094 Hom.: 0 AF XY: 0.000838 AC XY: 608 AN XY: 725820

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.0000456

Gnomad4 ASJ exome AF: 0.000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74352

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000912 Hom.: 0

Bravo AF: 0.000540

EpiCase AF: 0.000873

EpiControl AF: 0.00101

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 8, autosomal Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with heterotaxy, visceral, 8 (MIM#617205). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (96 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable canonical splice variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in homozygous and compound heterozygous individuals with features including heterotaxy, congenital heart defects, intestinal malroation and biliary atresia (ClinVar, PMID: 30664273, PMID: 27616478, PMID: 32111882). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed in two homozygous siblings, and was heterozygous in their unaffected sibling and parents, however more meioses are required to establish the significance of this segregation (PMID: 27616478). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 30, 2023	- -

Situs inversus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 27, 2016

Pathogenicity based on finding the variant in the homozygous state in 2 individuals from one family, both with heterotaxy and complex congenital heart defect. -

PKD1L1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

The PKD1L1 c.6473+2_6473+3delTG variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported to be pathogenic for autosomal recessive autosomal visceral heterotaxy (Vetrini et al. 2016. PubMed ID: 27616478; Berauer et al. 2019. PubMed ID: 30664273; Normand et al. 2018. PubMed ID: 30266093). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.66		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs528302390; hg19: chr7-47870811;