rs121918705

Variant names:

• chr3-24122968-G-T
• rs121918705
• NM_001354712.2:c.1302C>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_001354712.2(THRB):​c.1302C>A​(p.Cys434*) variant causes a stop gained change. 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 (★). ClinVar reports functional evidence for this variant: "SCV000680762: Functional studies demonstrate a damaging effect with dominant negative activity, silencing of basal gene transcription, and abnormal DNA-binding properties (Behr et al., 1997).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRB NM_001354712.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.10
• Publications: 1 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 Gene-Disease associations (from GenCC):

• thyroid hormone resistance, generalized, autosomal dominant

  Inheritance: SD, AD Classification: STRONG Submitted by: PanelApp Australia, 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)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 31 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000680762: Functional studies demonstrate a damaging effect with dominant negative activity, silencing of basal gene transcription, and abnormal DNA-binding properties (Behr et al., 1997).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-24122968-G-T is Pathogenic according to our data. Variant chr3-24122968-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12565.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1302C>A	p.Cys434*	stop_gained	Exon 11 of 11	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.1302C>A	p.Cys434*	stop_gained	Exon 10 of 10	NP_000452.2
	THRB	NM_001128176.3		c.1302C>A	p.Cys434*	stop_gained	Exon 11 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.1302C>A	p.Cys434*	stop_gained	Exon 11 of 11	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.1302C>A	p.Cys434*	stop_gained	Exon 11 of 11	ENSP00000348827.4	P10828-1
	THRB	ENST00000280696.9	TSL:5	c.1347C>A	p.Cys449*	stop_gained	Exon 7 of 7	ENSP00000280696.5	P10828-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Thyroid hormone resistance, generalized, autosomal dominant (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.1
Vest4		0.84
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

dbSNP: rs121918705; hg19: chr3-24164459;