rs146519878
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_138694.4(PKHD1):c.9788T>C(p.Val3263Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,826 control chromosomes in the GnomAD database, including 14 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. V3263V) has been classified as Likely benign.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.9788T>C | p.Val3263Ala | missense_variant | 58/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.9788T>C | p.Val3263Ala | missense_variant | 58/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.9788T>C | p.Val3263Ala | missense_variant | 58/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00249 AC: 378AN: 152100Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00167 AC: 420AN: 251166Hom.: 1 AF XY: 0.00168 AC XY: 228AN XY: 135738
GnomAD4 exome AF: 0.00306 AC: 4468AN: 1461608Hom.: 10 Cov.: 33 AF XY: 0.00298 AC XY: 2168AN XY: 727120
GnomAD4 genome ? AF: 0.00248 AC: 378AN: 152218Hom.: 4 Cov.: 32 AF XY: 0.00226 AC XY: 168AN XY: 74414
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 04, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2017 | Variant summary: The PKHD1 c.9788T>C (p.Val3263Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 463/258028 control chromosomes (gnomAD), including 2 homozygotes, at a frequency of 0.0017944, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Clinical diagnostic laboratories/reputable databases classified this variant as likely benign and uncertain significance. The variant of interest has been reported in multiple patients with ARPKD (Melchionda_2016, Sharp_2005) and pathologies with partially overlapping renal phenotype, including one patient with dominantly inherited isolated polycystic liver disease (Besse_2017), all without strong evidence for causality. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until more definitive clinical and functional data become available. - |
Autosomal recessive polycystic kidney disease Uncertain:1Benign:1
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 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2020 | This variant is associated with the following publications: (PMID: 21228398, 15805161) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PKHD1: BP4 - |
Polycystic kidney disease Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1, p.Val3263Ala variant was identified in 2 of 274 proband chromosomes (frequency: 0.007) from individuals or families with ARPKD, and was not identified in 200 control chromosomes from healthy individuals (Sharp 2005, Gunay-Aygun 2010). The variant was also identified in dbSNP (ID: rs146519878) as “With Uncertain significance allele”, Clinvitae database (classified as unclassified variant by ClinVar and Invitae), the ClinVar database (classified as uncertain significance by Emory Genetics and Invitae), RWTH AAachen University ARPKD database (classified as probably benign) and PKHD1-LOVD (2x as unknown/not classified). This variant was identified in the 1000 Genomes Project in 6 of 5000 chromosomes (frequency: 0.0012), the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and in 1 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 210 (1 homozygous) of 121276 chromosomes (freq. 0.002) in the following populations: European in 193 of 66708 chromosomes (freq. 0.003), Latino in 7 of 11500 chromosomes (freq. 0.0006), African in 5 of 10406 chromosomes (freq. 0.0005), Finnish in 3 of 6612 chromosomes (freq. 0.0005), South Asian in 1 of 16512 chromosomes (freq. 0.00006), Other in 1 of 906 chromosomes (freq. 0.001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Val3263 residue is not 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 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a 5’ splice site that is not at the canonical 5’ splice site. However, this information is not predictive enough to assume pathogenicity. 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. - |
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 | - - |
PKHD1-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 09, 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at