rs142107837
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_138694.4(PKHD1):c.3367G>A(p.Gly1123Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1123D) has been classified as Uncertain significance.
Frequency
Consequence
NM_138694.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.3367G>A | p.Gly1123Ser | missense_variant, splice_region_variant | 30/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.3367G>A | p.Gly1123Ser | missense_variant, splice_region_variant | 30/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.3367G>A | p.Gly1123Ser | missense_variant, splice_region_variant | 30/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251316Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135824
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461032Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726820
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74306
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1123 of the PKHD1 protein (p.Gly1123Ser). This variant is present in population databases (rs142107837, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12506140, 12874454, 15698423, 15805161, 25966130; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188959). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 08, 2014 | - - |
Polycystic kidney disease 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 17, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24984783, 31589614, 25966130, 15805161, 12874454, 12506140, 15698423) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at