rs121918708

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_001354712.2(THRB):​c.1148G>A​(p.Arg383His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R383C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

THRB
NM_001354712.2 missense

Scores

16
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.91
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THRB. . Gene score misZ 2.5652 (greater than the threshold 3.09). Trascript score misZ 3.708 (greater than threshold 3.09). GenCC has associacion of gene with thyroid hormone resistance, generalized, autosomal dominant, resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 3-24123122-C-T is Pathogenic according to our data. Variant chr3-24123122-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12568.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
THRBNM_001354712.2 linkuse as main transcriptc.1148G>A p.Arg383His missense_variant 11/11 ENST00000646209.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THRBENST00000646209.2 linkuse as main transcriptc.1148G>A p.Arg383His missense_variant 11/11 NM_001354712.2 P10828-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151984
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251336
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151984
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74230
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 providedliterature onlyOMIMSep 01, 1999- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D;D;D;D;D;D;D;D;D;D;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
.;.;.;.;.;.;.;.;.;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
2.9
M;M;M;M;M;M;M;M;M;M;.
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-4.4
D;D;.;.;.;.;.;.;D;.;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;.;.;.;.;.;.;D;.;D
Sift4G
Uncertain
0.041
D;D;.;.;.;.;.;.;D;.;D
Polyphen
1.0
D;D;D;D;D;D;D;D;D;D;.
Vest4
0.79
MutPred
0.96
Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);Gain of glycosylation at S381 (P = 0.0999);.;
MVP
0.92
MPC
2.6
ClinPred
1.0
D
GERP RS
6.0
Varity_R
0.84
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918708; hg19: chr3-24164613; COSMIC: COSV54981749; API