rs41273726

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_138694.4(PKHD1):c.3407A>G(p.Tyr1136Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,614,058 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0084 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 103 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14

Conservation

PhyloP100: -0.0580

Variant links:

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010802239).

BP6

Variant 6-52028309-T-C is Benign according to our data. Variant chr6-52028309-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167489.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=7, Benign=3}. Variant chr6-52028309-T-C is described in Lovd as [Likely_benign]. Variant chr6-52028309-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00842 (1282/152242) while in subpopulation NFE AF= 0.014 (955/68004). AF 95% confidence interval is 0.0133. There are 11 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.3407A>G	p.Tyr1136Cys	missense_variant	30/67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.3407A>G	p.Tyr1136Cys	missense_variant	30/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.3407A>G	p.Tyr1136Cys	missense_variant	30/61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00843

AC:

1282

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0127

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00764

AC:

1921

AN:

251458

Hom.:

AF XY:

0.00737

AC XY:

1002

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00238

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00733

GnomAD4 exome

AF:

0.00846

AC:

12371

AN:

1461816

Hom.:

103

Cov.:

AF XY:

0.00865

AC XY:

6289

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00157

Gnomad4 ASJ exome

AF:

0.0161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00243

Gnomad4 FIN exome

AF:

0.0127

Gnomad4 NFE exome

AF:

0.00949

Gnomad4 OTH exome

AF:

0.00669

GnomAD4 genome

AF:

0.00842

AC:

1282

AN:

152242

Hom.:

Cov.:

AF XY:

0.00789

AC XY:

587

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0127

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00606

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.0102

AC:

ExAC

AF:

0.00790

AC:

959

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0117

EpiControl

AF:

0.00771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 30, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2017	Variant summary: The PKHD1 c.3407A>G (p.Tyr1136Cys) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not available). This variant was found in 960/121796 control chromosomes (14 homozygotes) at a frequency of 0.007882, which slightly exceeds the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this variant is likely a benign polymorphism. In the literature this variant was reported in multiple patients with ARPKD without strong evidence for causality. One reported patient had co-occurrence of a pathogenic variant PKHD1 c. 1458C>A, p.Tyr486X in cis, supporting the non-pathgoenic nature of the variant of interest (Gunay-Aygun_MGM_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as a likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PKHD1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	This variant is associated with the following publications: (PMID: 30343465, 15805161, 21228398) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2014	- -

Caroli disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II

May 05, 2021

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 p.Tyr1136Cys variant was identified in 1 of 450 proband chromosomes (frequency: 0.002) from individuals or families with ARPKD, and was present in 1 of 400 control chromosomes (frequency: 0.0025) from healthy individuals (Bergmann_2005, Losekoot_2005). The variant was identified in dbSNP (ID: rs41273726) with â€šÃ„Ãºotherâ€šÃ„Ã¹ allele, in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.0026) and in Exome Variant Server project in 88 of 8600 (frequency 0.01) in European American alleles and 3 of 4406 (frequency 0.0007) African American alleles. The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 959 of 121396 chromosomes of which 14 are homozygotes (frequency 0.0079); or 80 of 6612 European Finnish (frequency 0.0121), 797 of 66734 European non Finnish (frequency 0.01194), 37 of 16512 south Asians (frequency 0.002241), 22 of 11576 Latino (frequency 0.0019), 15 of 10404 African (frequency 0.01442), 1 of 8650 East Asians (frequency 0.0001) and 7 of 908 other (frequency 0.008). The variant was also listed in ClinVar 1x by Emory Genetics Laboratory and 1x by Invitae as benign and identified by Counsyl 1x as likely benign and in Clinvitae by EmyClass 1x as benign. The variant was also identified in RWTH AAachen University ARPKD database with conflicting interpretations: 6x as polymorphism, 11x as pathogenic and 13x as probably pathogenic with control frequency of 0% - 0.5%. The p.Tyr1136 residue is not entirely conserved in mammals and the variant amino acid Cystine is present in frog and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In addition this variant was seen co-occurring with a pathogenic variant (c.8095C>T, p.Gln2699X) in a patient with polycystic kidney disease. 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 likely benign. -

Polycystic kidney disease 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.5

DANN

Benign

0.94

DEOGEN2

Uncertain

0.73

D;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.22

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Benign

0.21

Sift

Benign

0.11

T;T

Sift4G

Uncertain

0.055

T;T

Polyphen

1.0

D;D

Vest4

0.38

MVP

0.91

MPC

0.075

ClinPred

0.050

GERP RS

0.46

Varity_R

0.12

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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