chr3-24373085-A-T

Variant names:

• chr3-24373085-A-T
• rs7642682
• NM_001354712.2:c.-260-35714T>A

Variant summary

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

The NM_000461.5(THRB):​c.-114-35714T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 151,920 control chromosomes in the GnomAD database, including 4,228 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 (4228 hom., cov: 32)
• Consequence: THRB NM_000461.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• 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: 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000461.5. 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.-260-35714T>A		intron	N/A	NP_001341641.1
	THRB	NM_000461.5		c.-114-35714T>A		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.-260-35714T>A		intron	N/A	NP_001121648.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.-260-35714T>A		intron	N/A	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.-260-35714T>A		intron	N/A	ENSP00000348827.4
	THRB	ENST00000447875.5	TSL:1	c.-251-35714T>A		intron	N/A	ENSP00000388467.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34318 AN: 151802 Hom.: 4216 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.226 AC: 34357 AN: 151920 Hom.: 4228 Cov.: 32 AF XY: 0.223 AC XY: 16559 AN XY: 74248

African (AFR) AF: 0.303 AC: 12543 AN: 41404

American (AMR) AF: 0.165 AC: 2515 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 619 AN: 3468

East Asian (EAS) AF: 0.0335 AC: 173 AN: 5164

South Asian (SAS) AF: 0.230 AC: 1104 AN: 4800

European-Finnish (FIN) AF: 0.174 AC: 1841 AN: 10574

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14800 AN: 67960

Other (OTH) AF: 0.215 AC: 454 AN: 2108

Alfa AF: 0.215 Hom.: 459

Bravo AF: 0.227

Asia WGS AF: 0.152 AC: 527 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.55
DANN	Benign	0.66
PhyloP100		-0.58
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: rs7642682; hg19: chr3-24414576;