rs17787283

Variant names:

• chr3-24232061-G-T
• rs17787283
• NM_001354712.2:c.-42-3060C>A

Variant summary

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

The NM_001354712.2(THRB):​c.-42-3060C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,092 control chromosomes in the GnomAD database, including 4,765 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 0.23 (4765 hom., cov: 32)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.592
• 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: 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-AS2 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.-42-3060C>A		intron	N/A	NP_001341641.1
	THRB	NM_000461.5		c.-42-3060C>A		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.-42-3060C>A		intron	N/A	NP_001121648.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.-42-3060C>A		intron	N/A	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.-42-3060C>A		intron	N/A	ENSP00000348827.4
	THRB	ENST00000447875.5	TSL:1	c.-42-3060C>A		intron	N/A	ENSP00000388467.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35716 AN: 151974 Hom.: 4764 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.258

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

GnomAD4 genome AF: 0.235 AC: 35732 AN: 152092 Hom.: 4765 Cov.: 32 AF XY: 0.233 AC XY: 17352 AN XY: 74332

African (AFR) AF: 0.119 AC: 4936 AN: 41514

American (AMR) AF: 0.198 AC: 3028 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1477 AN: 3472

East Asian (EAS) AF: 0.113 AC: 584 AN: 5172

South Asian (SAS) AF: 0.274 AC: 1319 AN: 4814

European-Finnish (FIN) AF: 0.297 AC: 3137 AN: 10576

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20445 AN: 67948

Other (OTH) AF: 0.256 AC: 539 AN: 2108

Alfa AF: 0.279 Hom.: 10670

Bravo AF: 0.223

Asia WGS AF: 0.200 AC: 698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.6
DANN	Benign	0.67
PhyloP100		0.59
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: rs17787283; hg19: chr3-24273552;