3-24124673-C-T

Variant names:

• chr3-24124673-C-T
• rs7609948
• NM_001354712.2:c.1145-1548G>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.1145-1548G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,090 control chromosomes in the GnomAD database, including 4,585 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 0.24 (4585 hom., cov: 32)
• Consequence: THRB NM_000461.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214
• Publications: 3 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.265 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.1145-1548G>A		intron	N/A	NP_001341641.1
	THRB	NM_000461.5		c.1145-1548G>A		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.1145-1548G>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.1145-1548G>A		intron	N/A	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.1145-1548G>A		intron	N/A	ENSP00000348827.4
	THRB	ENST00000280696.9	TSL:5	c.1190-1548G>A		intron	N/A	ENSP00000280696.5

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36666 AN: 151972 Hom.: 4590 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.242

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

GnomAD4 genome AF: 0.241 AC: 36670 AN: 152090 Hom.: 4585 Cov.: 32 AF XY: 0.239 AC XY: 17805 AN XY: 74348

African (AFR) AF: 0.218 AC: 9052 AN: 41484

American (AMR) AF: 0.248 AC: 3794 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 984 AN: 3468

East Asian (EAS) AF: 0.0505 AC: 262 AN: 5186

South Asian (SAS) AF: 0.277 AC: 1335 AN: 4820

European-Finnish (FIN) AF: 0.250 AC: 2641 AN: 10568

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17901 AN: 67980

Other (OTH) AF: 0.238 AC: 503 AN: 2114

Alfa AF: 0.254 Hom.: 1023

Bravo AF: 0.237

Asia WGS AF: 0.151 AC: 525 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.8
DANN	Benign	0.78
PhyloP100		0.21
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: rs7609948; hg19: chr3-24166164;