rs367678592
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_138694.4(PKHD1):āc.9146A>Gā(p.His3049Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.000013 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
12
7
Clinical Significance
Conservation
PhyloP100: 3.95
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a repeat PbH1 8 (size 22) in uniprot entity PKHD1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_138694.4
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.9146A>G | p.His3049Arg | missense_variant | 58/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.9146A>G | p.His3049Arg | missense_variant | 58/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.9146A>G | p.His3049Arg | missense_variant | 58/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251028Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135654
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461700Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727146
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2023 | The c.9146A>G (p.H3049R) alteration is located in exon 58 (coding exon 57) of the PKHD1 gene. This alteration results from an A to G substitution at nucleotide position 9146, causing the histidine (H) at amino acid position 3049 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (3/251028) total alleles studied. The highest observed frequency was 0.003% (3/113480) of European (non-Finnish) alleles. This variant has been reported in trans with a second PKHD1 variant in multiple individuals diagnosed with autosomal recessive polycystic kidney disease (Gunay-Aygun, 2010). This amino acid position is well conserved in available mammalian species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Polycystic kidney disease Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.His3049Arg variant was identified in 4 of 166 proband chromosomes (frequency: 0.024) from individuals or families with ARPKD and was not identified in 400 control chromosomes from healthy individuals (Gunay-Aygun 2010, Tong 2016). The variant was also identified in dbSNP (ID: rs367678592) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by Ambry Genetics), LOVD 3.0, and in RWTH AAachen University ARPKD database (possibly pathogenic). The variant was identified in control databases in 4 of 245786 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 4 of 111412 chromosomes (freq: 0.000036), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.His3049 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. - |
Autosomal recessive polycystic kidney disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. ClinVar contains an entry for this variant (Variation ID: 522152). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 19914852, 20413436, 31395954). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs367678592, gnomAD 0.004%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 3049 of the PKHD1 protein (p.His3049Arg). - |
Polycystic kidney disease 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 23, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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