3-24462263-G-C

Variant names:

• chr3-24462263-G-C
• rs2362186
• NM_001354712.2:c.-261+32389C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354712.2(THRB):​c.-261+32389C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,010 control chromosomes in the GnomAD database, including 15,047 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (15047 hom., cov: 33)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0430
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.558 is higher than 0.05.

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.-261+32389C>G		intron	N/A	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.-115+32389C>G		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.-261+32424C>G		intron	N/A	NP_001121648.1	P10828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.-261+32389C>G		intron	N/A	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.-261+32424C>G		intron	N/A	ENSP00000348827.4	P10828-1
	THRB	ENST00000447875.5	TSL:1	c.-323-32091C>G		intron	N/A	ENSP00000388467.1	A0A0C4DG57

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66276 AN: 151892 Hom.: 15016 Cov.: 33

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.413

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.437 AC: 66359 AN: 152010 Hom.: 15047 Cov.: 33 AF XY: 0.432 AC XY: 32074 AN XY: 74280

African (AFR) AF: 0.564 AC: 23366 AN: 41462

American (AMR) AF: 0.355 AC: 5432 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3468

East Asian (EAS) AF: 0.444 AC: 2293 AN: 5160

South Asian (SAS) AF: 0.500 AC: 2412 AN: 4824

European-Finnish (FIN) AF: 0.307 AC: 3231 AN: 10540

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.394 AC: 26737 AN: 67938

Other (OTH) AF: 0.415 AC: 877 AN: 2112

Alfa AF: 0.425 Hom.: 1697

Bravo AF: 0.445

Asia WGS AF: 0.488 AC: 1697 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.3
DANN	Benign	0.31
PhyloP100		0.043
Mutation Taster		=100/0	polymorphism (auto)

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: rs2362186; hg19: chr3-24503754;