rs41290646
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000316.3(PTH1R):c.299G>A(p.Gly100Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,322 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000316.3 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 |
---|---|---|---|---|---|---|---|
PTH1R | NM_000316.3 | c.299G>A | p.Gly100Asp | missense_variant | 5/16 | ENST00000449590.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTH1R | ENST00000449590.6 | c.299G>A | p.Gly100Asp | missense_variant | 5/16 | 1 | NM_000316.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00218 AC: 332AN: 152052Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00202 AC: 508AN: 251102Hom.: 2 AF XY: 0.00200 AC XY: 271AN XY: 135736
GnomAD4 exome AF: 0.00207 AC: 3028AN: 1461150Hom.: 14 Cov.: 32 AF XY: 0.00209 AC XY: 1519AN XY: 726884
GnomAD4 genome ? AF: 0.00218 AC: 331AN: 152172Hom.: 1 Cov.: 32 AF XY: 0.00202 AC XY: 150AN XY: 74400
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 17, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 10, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PTH1R p.Gly100Asp variant was identified in 1 of 168 proband chromosomes (frequency: 0.00595) from individuals with Ollier disease and was present in 1 of 444 control chromosomes (frequency: 0.00225) from healthy individuals (Couvineau_2008_PMID:18559376). The variant was identified in dbSNP (ID: rs41290646), LOVD 3.0 and ClinVar (classified as likely benign by Illumina and Center for Pediatric Genomic Medicine, and as benign by Invitae). The variant was identified in control databases in 563 of 282480 chromosomes (2 homozygous) at a frequency of 0.001993 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 471 of 128948 chromosomes (freq: 0.003653), Other in 15 of 7214 chromosomes (freq: 0.002079), European (Finnish) in 29 of 25098 chromosomes (freq: 0.001155), Latino in 38 of 35402 chromosomes (freq: 0.001073), Ashkenazi Jewish in 3 of 10362 chromosomes (freq: 0.00029), African in 5 of 24916 chromosomes (freq: 0.000201) and South Asian in 2 of 30598 chromosomes (freq: 0.000065), but was not observed in the East Asian population. The p.Gly100 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. Functional in vitro assays demonstrated that the p.Gly100Asp variant results in <5% ligand binding compared to wildtype, however localization and receptor function was not affected by the variant, suggesting no functional effect (Couvineau_2008_PMID:18559376). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 31, 2018 | - - |
Chondrodysplasia Blomstrand type Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Metaphyseal chondrodysplasia, Jansen type Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at