rs1554218666
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_138694.4(PKHD1):c.9370C>T(p.His3124Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3124P) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 6.54
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr6-51748245-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067981.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.904
PP5
?
Variant 6-51748246-G-A is Pathogenic according to our data. Variant chr6-51748246-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51748246-G-A is described in Lovd as [Pathogenic]. Variant chr6-51748246-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.9370C>T | p.His3124Tyr | missense_variant | 58/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.9370C>T | p.His3124Tyr | missense_variant | 58/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.9370C>T | p.His3124Tyr | missense_variant | 58/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. ClinVar contains an entry for this variant (Variation ID: 555142). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12874454, 15108281, 31844813, 32398770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 3124 of the PKHD1 protein (p.His3124Tyr). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics, Children's Memorial Health Institute | Sep 25, 2020 | - - |
Polycystic kidney disease 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 24, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at