rs371510537

Positions:

• chr6-51847975-A-C
• chr6-51847975-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.7912-5T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,606,658 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (9 hom.)
• Consequence: PKHD1 NM_138694.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.2180
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 0.486

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-51847975-A-C is Benign according to our data. Variant chr6-51847975-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96425.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000813 (1183/1454378) while in subpopulation MID AF= 0.0235 (135/5754). AF 95% confidence interval is 0.0202. There are 9 homozygotes in gnomad4_exome. There are 628 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.7912-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.7912-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.7912-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00104 AC: 262 AN: 250930 Hom.: 0 AF XY: 0.00119 AC XY: 162 AN XY: 135630

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.000813 AC: 1183 AN: 1454378 Hom.: 9 Cov.: 29 AF XY: 0.000867 AC XY: 628 AN XY: 724076

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000627

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74468

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000758 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKHD1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2023	BP4 -

Autosomal recessive polycystic kidney disease Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Polycystic kidney disease 4 Uncertain:1

Uncertain significance, flagged submission

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 01, 2020

- -

PKHD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.8
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.22
dbscSNV1_RF	Benign	0.43
SpliceAI score (max)		0.17		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: rs371510537; hg19: chr6-51712773;