3-24143539-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001354712.2(THRB):c.700G>A(p.Ala234Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A234V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THRB
NM_001354712.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.91

Publications

8 publications found

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]

THRB Gene-Disease associations (from GenCC):

thyroid hormone resistance, generalized, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hormone resistance, generalized, autosomal recessive
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

THRB links:

THRB-AS2 (HGNC:):

THRB-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the THRB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.5652 (below the threshold of 3.09). Trascript score misZ: 3.708 (above the threshold of 3.09). GenCC associations: The gene is linked to resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive, thyroid hormone resistance, generalized, autosomal dominant.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.843

PP5

Variant 3-24143539-C-T is Pathogenic according to our data. Variant chr3-24143539-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2 link	c.700G>A	p.Ala234Thr	missense_variant	Exon 8 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2 link	c.700G>A	p.Ala234Thr	missense_variant	Exon 8 of 11		NM_001354712.2	ENSP00000496686.2		P10828-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jun 22, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, the variant has been reported to segregate with disease in families affected with resistance to thyroid hormone, and functional studies indicate this variant results in a hormone binding defect (PMID: 9804773 (1998), 1324420 (1992), 25040256 (2014), 26273722 (2015)). -

Thyroid hormone resistance, generalized, autosomal dominant

Pathogenic:1

May 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Thyroid hormone resistance syndrome

Pathogenic:1

Jun 16, 2017

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;D;D;D;D;D;D;D;D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;.;.;.;.;.;.;.;.;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.4

M;M;M;M;M;M;M;M;M;M;.

PhyloP100

7.9

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

N;N;.;.;.;.;.;.;N;.;N

REVEL

Pathogenic

0.72

Sift

Uncertain

0.013

D;D;.;.;.;.;.;.;D;.;D

Sift4G

Benign

0.33

T;T;.;.;.;.;.;.;T;.;T

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D;.

Vest4

0.72

MutPred

0.54

Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);Loss of MoRF binding (P = 0.1115);.;

MVP

0.81

MPC

1.2

ClinPred

0.93

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.49

gMVP

0.79

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over