rs121918699

Positions:

• chr3-24127714-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001354712.2(THRB):​c.929T>C​(p.Met310Thr) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRB	NM_001354712.2	c.929T>C	p.Met310Thr	missense_variant	10/11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.929T>C	p.Met310Thr	missense_variant	10/11		NM_001354712.2	ENSP00000496686

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized resistance to thyroid hormone Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1994

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 07, 2022

Variant summary: THRB c.929T>C (p.Met310Thr) results in a non-conservative amino acid change located in the Nuclear hormone receptor, ligand-binding domain (IPR000536) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251438 control chromosomes (gnomAD). c.929T>C has been reported in the literature in at least two heterozygous individuals affected with Generalized, Autosomal Dominant Thyroid Hormone Resistance (Takeda_1992, Kim_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L;L;L;L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Uncertain	0.010	D;D;.;.;.;.;.;.;D;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.97
MutPred		0.83		Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);Loss of glycosylation at K306 (P = 0.0872);.;
MVP		0.93
MPC		2.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.92
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs121918699; hg19: chr3-24169205; COSMIC: COSV99769777;