3-24152410-T-C

Variant names:

• chr3-24152410-T-C
• NM_001354712.2:c.364A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001354712.2(THRB):​c.364A>G​(p.Ile122Val) 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: 32)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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-AS2 (HGNC:):

THRB-AS2 (HGNC:54854): (THRB antisense RNA 2)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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, 0.849

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354712.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.364A>G	p.Ile122Val	missense	Exon 6 of 11	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.364A>G	p.Ile122Val	missense	Exon 5 of 10	NP_000452.2
	THRB	NM_001128176.3		c.364A>G	p.Ile122Val	missense	Exon 6 of 11	NP_001121648.1	P10828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.364A>G	p.Ile122Val	missense	Exon 6 of 11	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.364A>G	p.Ile122Val	missense	Exon 6 of 11	ENSP00000348827.4	P10828-1
	THRB	ENST00000447875.5	TSL:1	c.364A>G	p.Ile122Val	missense splice_region	Exon 7 of 7	ENSP00000388467.1	A0A0C4DG57

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.3	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.36	N
REVEL	Pathogenic	0.73
Sift	Benign	0.038	D
Sift4G	Benign	0.070	T
Polyphen		0.98	D
Vest4		0.44
MutPred		0.62		Gain of glycosylation at T123 (P = 0.188)
MVP		0.83
MPC		2.0
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.21
gMVP		0.80
Mutation Taster		=17/83	disease causing

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

Other links and lift over

hg19: chr3-24193901; COSMIC: COSV54981952; COSMIC: COSV54981952;