rs140980374
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001009944.3(PKD1):c.4264G>A(p.Ala1422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,611,388 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.4264G>A | p.Ala1422Thr | missense_variant | 15/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.4264G>A | p.Ala1422Thr | missense_variant | 15/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.00499 AC: 759AN: 152184Hom.: 4 Cov.: 33
GnomAD3 exomes AF: 0.00591 AC: 1472AN: 248902Hom.: 12 AF XY: 0.00603 AC XY: 816AN XY: 135334
GnomAD4 exome AF: 0.00549 AC: 8012AN: 1459086Hom.: 48 Cov.: 36 AF XY: 0.00550 AC XY: 3989AN XY: 725832
GnomAD4 genome ? AF: 0.00498 AC: 758AN: 152302Hom.: 4 Cov.: 33 AF XY: 0.00485 AC XY: 361AN XY: 74462
ClinVar
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2020 | This variant is associated with the following publications: (PMID: 17582161, 22383692) - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PKD1: BP4, BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Polycystic kidney disease, adult type Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 20, 2019 | - - |
Polycystic kidney disease Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | PKD1, EXON15, c.4264G>A, p.Ala1422Thr, (Alias c.4475G>A), Heterozygous, Benign The PKD1 p.Ala1422Thr variant was identified in 3 of 864 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD, and was not identified in 242 control chromosomes from healthy individuals (Rossetti 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs140980374) “With clinical significance allele not available”, in 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.004), in NHLBI GO Exome Sequencing Project (ESP) in 72 of 8592 European American (frequency: 0.008) and 9 in 4394 (frequency: 0.002) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 2016) in 713 (5 homozygous) of 118566 chromosomes (freq. 0.006) in the following populations: other in 10 of 880 chromosomes (freq. 0.01), European (Non-Finnish) in 565 of 64594 chromosomes (freq. 0.009), South Asian in 76 of 16504 chromosomes (freq. 0.005), Latino in 45 of 11538 chromosomes (freq. 0.004), Finnish in 7 of 6602 chromosomes (freq. 0.001), and African in 10 of 9854 chromosomes (freq. 0.001), but was not seen in the East Asian populations, increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. Furthermore, the variant is listed in the GeneInsight COGR database as benign, as likely neutral in the ADPKD Mutation Database, and listed with no classification in the PKD1-LOVD 3.0 database. The p.Ala1422 residue is not conserved in mammals and 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. Furthermore, the variant amino acid “Threonine” is present in macaque, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was observed as co-occurring with another pathogenic variant in one individual identified by our laboratory, increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. - |
Autosomal dominant polycystic kidney disease Benign:1
Likely benign, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
PKD1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 05, 2019 | This variant is classified as 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