14-81092611-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_000369.5(TSHR):c.545+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000369.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSHR | NM_000369.5 | c.545+3G>C | splice_region_variant, intron_variant | Intron 6 of 9 | ENST00000298171.7 | NP_000360.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSHR | ENST00000298171.7 | c.545+3G>C | splice_region_variant, intron_variant | Intron 6 of 9 | 1 | NM_000369.5 | ENSP00000298171.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251324Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135828
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Hypothyroidism due to TSH receptor mutations Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1998 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2023 | Identified with a second TSHR variant, phase unknown, in a patient with hypothyroidisim in the published literature (Gagne et al., 1998); Published RT-PCR studies of this variant demonstrate that this variant leads to abnormal splicing (Gagne et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9589691) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at