rs148932323
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_138694.4(PKHD1):c.9866G>T(p.Ser3289Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,609,574 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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PKHD1 | ENST00000371117.8 | c.9866G>T | p.Ser3289Ile | missense_variant | Exon 59 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.9866G>T | p.Ser3289Ile | missense_variant | Exon 59 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.00311 AC: 473AN: 152038Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00321 AC: 801AN: 249686Hom.: 3 AF XY: 0.00321 AC XY: 433AN XY: 134984
GnomAD4 exome AF: 0.00442 AC: 6448AN: 1457418Hom.: 9 Cov.: 29 AF XY: 0.00426 AC XY: 3090AN XY: 725184
GnomAD4 genome AF: 0.00311 AC: 473AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00285 AC XY: 212AN XY: 74400
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:1Benign:4
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. -
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not provided Uncertain:1Benign:2
PKHD1: BS2 -
This variant is associated with the following publications: (PMID: 15805161, 21228398, 15108277) -
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not specified Benign:2
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Autosomal dominant polycystic liver disease Uncertain:1
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Polycystic kidney disease 4 Uncertain:1
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Polycystic kidney disease Benign:1
The PKHD1 p.Ser3289Ile variant was identified in 1 of 118 proband chromosomes (freq: 0.008) of individuals with autosomal recessive polycystic kidney disease (Sharp 2005). The variant was identified in dbSNP (rs148932323) as “with likely pathogenic allele”, ClinVar (interpreted as "likely benign" by Counsyl and 1 other, "benign" by Invitae and 1 other and "likely pathogenic" by GeneDx) and LOVD 3.0 (observed 6x). The variant was identified in control databases in 871 of 275,506 chromosomes (3 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 26 of 23,974 chromosomes (freq: 0.001), Other in 29 of 6406 chromosomes (freq: 0.005), Latino in 83 of 34,232 chromosomes (freq: 0.002), European in 599 of 125770 chromosomes (freq: 0.005), Ashkenazi Jewish in 1 of 10110 chromosomes (freq: 0.0001), Finnish in 120 of 25,664 chromosomes (freq: 0.004676), and South Asian in 13 of 30562 chromosomes (freq: 0.0005). The variant was not observed in the East Asian population. The p.Ser3289 residue is 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. Assessment Date: 2019/08/09 -
PKHD1-related disorder Benign:1
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