rs1505289

Variant names:

• chr3-24370365-T-C
• rs1505289
• NM_001354712.2:c.-260-32994A>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.-260-32994A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 151,776 control chromosomes in the GnomAD database, including 17,087 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 0.47 (17087 hom., cov: 31)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.512
• 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.-260-32994A>G		intron_variant	Intron 1 of 10	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.-260-32994A>G		intron_variant	Intron 1 of 10		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71180 AN: 151658 Hom.: 17064 Cov.: 31

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.435

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

GnomAD4 genome AF: 0.470 AC: 71259 AN: 151776 Hom.: 17087 Cov.: 31 AF XY: 0.473 AC XY: 35101 AN XY: 74146

African (AFR) AF: 0.525 AC: 21718 AN: 41376

American (AMR) AF: 0.487 AC: 7424 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1499 AN: 3460

East Asian (EAS) AF: 0.491 AC: 2503 AN: 5100

South Asian (SAS) AF: 0.460 AC: 2203 AN: 4792

European-Finnish (FIN) AF: 0.534 AC: 5632 AN: 10546

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28911 AN: 67940

Other (OTH) AF: 0.435 AC: 917 AN: 2108

Alfa AF: 0.439 Hom.: 12541

Bravo AF: 0.469

Asia WGS AF: 0.435 AC: 1516 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.41
PhyloP100		-0.51
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: rs1505289; hg19: chr3-24411856;