rs121918688
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_001354712.2(THRB):c.1020G>C(p.Gln340His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
THRB
NM_001354712.2 missense
NM_001354712.2 missense
Scores
9
7
2
Clinical Significance
Conservation
PhyloP100: 2.77
Genes affected
THRB (HGNC:11799): (thyroid hormone receptor beta) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001354712.2
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, THRB
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
?
Variant 3-24127623-C-G is Pathogenic according to our data. Variant chr3-24127623-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12536.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
THRB | NM_001354712.2 | c.1020G>C | p.Gln340His | missense_variant | 10/11 | ENST00000646209.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
THRB | ENST00000646209.2 | c.1020G>C | p.Gln340His | missense_variant | 10/11 | NM_001354712.2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1994 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;D;D;D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M;M;M;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;.;.;.;.;.;D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;.;.;.;.;D;.;D
Sift4G
Benign
T;T;.;.;.;.;.;.;T;.;T
Polyphen
D;D;D;D;D;D;D;D;D;D;.
Vest4
MutPred
Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);Gain of catalytic residue at R338 (P = 0.0482);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at