rs148932323

chr6-51746853-C-Achr6-51746853-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):c.9866G>T(p.Ser3289Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,609,574 control chromosomes in the GnomAD database, including 9 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. S3289S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (9 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:10
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03381604).
• BP6: Variant 6-51746853-C-A is Benign according to our data. Variant chr6-51746853-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167475.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=5, Uncertain_significance=3}. Variant chr6-51746853-C-A is described in Lovd as [Likely_benign]. Variant chr6-51746853-C-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.9866G>T	p.Ser3289Ile	missense_variant	59/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.9866G>T	p.Ser3289Ile	missense_variant	59/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.9866G>T	p.Ser3289Ile	missense_variant	59/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00567

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00321 AC: 801 AN: 249686 Hom.: 3 AF XY: 0.00321 AC XY: 433 AN XY: 134984

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000428

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00442 AC: 6448 AN: 1457418 Hom.: 9 Cov.: 29 AF XY: 0.00426 AC XY: 3090 AN XY: 725184

Gnomad4 AFR exome AF: 0.000958

Gnomad4 AMR exome AF: 0.00269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000525

Gnomad4 FIN exome AF: 0.00485

Gnomad4 NFE exome AF: 0.00518

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74400

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.00459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00567

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00405 Hom.: 2

Bravo AF: 0.00326

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00325 AC: 394

EpiCase AF: 0.00422

EpiControl AF: 0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	literature only	Counsyl	May 01, 2014	- -
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 30, 2017	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PKHD1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2020	This variant is associated with the following publications: (PMID: 15805161, 21228398, 15108277) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2016	- -

Autosomal dominant polycystic liver disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

Polycystic kidney disease 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1 p.Ser3289Ile variant was identified in 1 of 118 proband chromosomes (freq: 0.008) of individuals with autosomal recessive polycystic kidney disease (Sharp 2005). The variant was identified in dbSNP (rs148932323) as “with likely pathogenic allele”, ClinVar (interpreted as "likely benign" by Counsyl and 1 other, "benign" by Invitae and 1 other and "likely pathogenic" by GeneDx) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 871 of 275,506 chromosomes (3 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 26 of 23,974 chromosomes (freq: 0.001), Other in 29 of 6406 chromosomes (freq: 0.005), Latino in 83 of 34,232 chromosomes (freq: 0.002), European in 599 of 125770 chromosomes (freq: 0.005), Ashkenazi Jewish in 1 of 10110 chromosomes (freq: 0.0001), Finnish in 120 of 25,664 chromosomes (freq: 0.004676), and South Asian in 13 of 30562 chromosomes (freq: 0.0005). The variant was not observed in the East Asian population. The p.Ser3289 residue is conserved in mammals 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. Assessment Date: 2019/08/09 -

PKHD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.034	T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0090	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MVP		0.93
MPC		0.34
ClinPred		0.023	T
GERP RS		4.0
Varity_R		0.16
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs148932323; hg19: chr6-51611651; COSMIC: COSV61866082;