rs35445653

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.9577G>A(p.Val3193Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,004 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 75 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 61 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.414

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
polycystic kidney disease 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
Caroli disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034235418).

BP6

Variant 6-51748039-C-T is Benign according to our data. Variant chr6-51748039-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.9577G>A	p.Val3193Ile	missense_variant	Exon 58 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.9577G>A	p.Val3193Ile	missense_variant	Exon 58 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.9577G>A	p.Val3193Ile	missense_variant	Exon 58 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2573

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00714

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00503

AC:

1262

AN:

250900

AF XY:

0.00364

show subpopulations

Gnomad AFR exome

AF:

0.0623

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000441

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00190

AC:

2784

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1233

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0580

AC:

1941

AN:

33466

American (AMR)

AF:

0.00535

AC:

239

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.000533

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000255

AC:

284

AN:

1111950

Other (OTH)

AF:

0.00394

AC:

238

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

196

391

587

782

978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0169

AC:

2574

AN:

152228

Hom.:

Cov.:

AF XY:

0.0166

AC XY:

1235

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0580

AC:

2407

AN:

41534

American (AMR)

AF:

0.00713

AC:

109

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68006

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

236

355

473

591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0117

Hom.:

779

Bravo

AF:

0.0200

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0554

AC:

244

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00591

AC:

718

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 09, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PKHD1 c.9577G>A (p.Val3193Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant was found in 720/121508 control chromosomes (including 12 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0612736 (637/10396). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). As this variant exceeds allele frequency of 5% in African population, it can be regarded a common benign polymorphism found in the populations of African origin. It has also been published as a polymorphism in literature from in a ARPKD patient/normal controls (Sharp_2005). In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign. -

Jun 23, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15698423) -

Sep 29, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive polycystic kidney disease

Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKHD1 p.Val3193Ile variant was identified in 2 of 446 proband chromosomes (frequency: 0.004) from individuals with autosomal recessive polycystic kidney disease and 5 of 600 chromosomes (frequency: 0.008) from health individuals (Sharp 2005, Bergmann 2005). The variant was identified in dbSNP (rs35445653) as â€šÃ„Ãºother alleleâ€šÃ„Ã¹, ClinVar (classified as benign by Invitae, Integrated Genetics, Prevention Genetics and Children Mercy Hospital and likely benign by Illumina) an LOVD 3.0 (observed 2x). The variant was identified in control databases in 1787 of 282,242 chromosomes (38 homozygous) at a frequency of 0.006 (Genome Aggregation Database Feb 27, 2017) increasing the likelihood this could be a low frequency benign variant. The variant was observed in the following populations: African in 1522 of 24,938 chromosomes (freq: 0.06), Latino in 165 of 35,380 chromosomes (freq: 0.005), Other in 26 of 7208 chromosomes (freq: 0.004), South Asian in 11 of 30,616 chromosomes (freq: 0.0004), European in 57 of 128,682 chromosomes (freq: 0.0004), and East Asian in 6 of 19,946 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish or Finnish populations. The p.Val3193 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.036

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.083

T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.14

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.4

N;N

PhyloP100

-0.41

PrimateAI

Benign

0.25

PROVEAN

Benign

0.14

N;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.10

MVP

0.53

MPC

0.051

ClinPred

0.0050

GERP RS

-4.3

Varity_R

0.022

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over