rs139945204

Positions:

chr16-2100465-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_001009944.3(PKD1):c.9499A>T(p.Ile3167Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,874 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I3167I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:3

Conservation

PhyloP100: 1.45

Variant links:

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain PLAT (size 115) in uniprot entity PKD1_HUMAN there are 51 pathogenic changes around while only 15 benign (77%) in NM_001009944.3

BP4

Computational evidence support a benign effect (MetaRNN=0.39640847).

BS2

High AC in GnomAd4 at 181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.9499A>T	p.Ile3167Phe	missense_variant	27/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.9499A>T	p.Ile3167Phe	missense_variant	27/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000994

AC:

248

AN:

249424

Hom.:

AF XY:

0.000967

AC XY:

131

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00189

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.00107

AC:

1560

AN:

1458564

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

799

AN XY:

725602

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000580

Gnomad4 FIN exome

AF:

0.00194

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.000532

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152310

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00238

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.000824

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00109

AC:

132

EpiCase

AF:

0.00180

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	PKD1: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2023	Observed multiple times with a truncating variant on the opposite allele (in trans) in unrelated patients with in utero or early childhood presentation of polycystic kidney disease; often inherited from a presumably unaffected parent, suggesting that p.(I3167F) is a hypomorphic allele resulting in severe disease in compound heterozygous individuals (Mantovani et al., 2020; Durkie et al., 2021; Janssens et al., 2021); Identified in individuals with autosomal dominant polycystic kidney disease in published literature, however, familial segregation data and in vitro functional studies were not included (Rossetti et al., 2002; Neumann et al., 2013; Solazzo et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33168999, 23300259, 29338003, 11967008, 32457805, 34169210, 34426522, 34974531, 35327948, 37372410, 37231942, 37635794) -

Polycystic kidney disease, adult type

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Mar 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	North East Yorkshire Genomic Laboratory Hub	May 20, 2024	Unusual hypomorphic variant that is common in population but causes very severe early onset PKD when inherited in trans with another variant: https://doi.org/10.1155/2023/5597005 Durkie et al. shows this variant is found in 10 VEO-PKD cases from 7 families. New paper shows also in trans Smogavex et al. 2022 so 8 families. this is LIKELY HYPOMOPHIC VARIANT associated with VEO-PKD when in trans with 2nd variant (hypomorphic/LP/P). It does NOT cause cysts in isolation so should not be reported in isolation in the context of adult-onset ADPKD -

Polycystic kidney disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ile3167Phe variant was identified in 1 of 90 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Rossetti_2002_11967008). The variant was also identified in dbSNP (ID: rs139945204) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by ARUP), LOVD 3.0 (1X) and ADPKD Mutation Database (as indeterminate), and was not identified in GeneInsight-COGR and PKD1-LOVD. The variant was identified in control databases in 333 (1 homozygous) of 276076 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 7 of 6438 chromosomes (freq: 0.001), Latino in 2 of 34416 chromosomes (freq: 0.00006), European Non-Finnish in 262 (1 homozygous) of 125774 chromosomes (freq: 0.002), European Finnish in 42 of 25790 chromosomes (freq: 0.002), and South Asian in 20 of 30774 chromosomes (freq: 0.0007) while not observed in the African, Ashkenazi Jewish and East Asian population. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ile3167 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Phe to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

PKD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2023

The PKD1 c.9499A>T variant is predicted to result in the amino acid substitution p.Ile3167Phe. This variant has been reported in patients with autosomal dominant polycystic kidney disease (ADPKD), often in the compound heterozygous state with a pathogenic variant present on the other PKD1 allele (Mantovani et al. 2020. PubMed ID: 32457805; Durkie et al. 2021. PubMed ID: 33168999; Janssens et al. 2021. PubMed ID: 34169210; Smogavec et al. 2022. PubMed ID: 34974531). It is listed as “uncertain” and commented as possibly a modifier or weak variant in an ADPKD-specific variant database (http://pkdb.mayo.edu/) and is suspected to possibly be a hypomorphic variant (Mantovani et al. 2020. PubMed ID: 32457805; Durkie et al. 2021. PubMed ID: 33168999). In ClinVar, this variant is interpreted as likely benign or uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/440135/). Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal dominant polycystic kidney disease

Benign:1

Likely benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.42

T;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.026

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.91

MVP

0.92

ClinPred

0.10

GERP RS

-0.022

Varity_R

0.44

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over