3-24371199-G-A

Variant names:

• chr3-24371199-G-A
• rs1505287
• NM_001354712.2:c.-260-33828C>T

Variant summary

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

The NM_001354712.2(THRB):​c.-260-33828C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 151,742 control chromosomes in the GnomAD database, including 8,496 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 0.30 (8496 hom., cov: 31)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.467 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.-260-33828C>T		intron	N/A	NP_001341641.1
	THRB	NM_000461.5		c.-114-33828C>T		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.-260-33828C>T		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.-260-33828C>T		intron	N/A	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.-260-33828C>T		intron	N/A	ENSP00000348827.4
	THRB	ENST00000447875.5	TSL:1	c.-251-33828C>T		intron	N/A	ENSP00000388467.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45876 AN: 151622 Hom.: 8490 Cov.: 31

Gnomad AFR AF: 0.0941

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.302 AC: 45896 AN: 151742 Hom.: 8496 Cov.: 31 AF XY: 0.312 AC XY: 23136 AN XY: 74122

African (AFR) AF: 0.0940 AC: 3896 AN: 41456

American (AMR) AF: 0.386 AC: 5876 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 918 AN: 3466

East Asian (EAS) AF: 0.483 AC: 2482 AN: 5144

South Asian (SAS) AF: 0.428 AC: 2059 AN: 4808

European-Finnish (FIN) AF: 0.510 AC: 5374 AN: 10536

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24418 AN: 67808

Other (OTH) AF: 0.274 AC: 576 AN: 2106

Alfa AF: 0.335 Hom.: 2076

Bravo AF: 0.281

Asia WGS AF: 0.390 AC: 1357 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.6
DANN	Benign	0.46
PhyloP100		1.0
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: rs1505287; hg19: chr3-24412690;