3-24226945-A-G

Variant names:

• chr3-24226945-A-G
• rs826221
• NM_001354712.2:c.22+1993T>C

Variant summary

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

The NM_001354712.2(THRB):​c.22+1993T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 150,472 control chromosomes in the GnomAD database, including 1,281 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 0.11 (1281 hom., cov: 33)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144
• Publications: 2 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 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.22+1993T>C		intron	N/A	NP_001341641.1
	THRB	NM_000461.5		c.22+1993T>C		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.22+1993T>C		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.22+1993T>C		intron	N/A	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.22+1993T>C		intron	N/A	ENSP00000348827.4
	THRB	ENST00000447875.5	TSL:1	c.22+1993T>C		intron	N/A	ENSP00000388467.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16390 AN: 150352 Hom.: 1272 Cov.: 33

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0854

Gnomad OTH AF: 0.121

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

GnomAD4 genome AF: 0.109 AC: 16425 AN: 150472 Hom.: 1281 Cov.: 33 AF XY: 0.113 AC XY: 8302 AN XY: 73550

African (AFR) AF: 0.0770 AC: 3067 AN: 39824

American (AMR) AF: 0.249 AC: 3803 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 224 AN: 3472

East Asian (EAS) AF: 0.276 AC: 1427 AN: 5170

South Asian (SAS) AF: 0.133 AC: 644 AN: 4830

European-Finnish (FIN) AF: 0.104 AC: 1099 AN: 10606

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0854 AC: 5806 AN: 68014

Other (OTH) AF: 0.128 AC: 268 AN: 2098

Alfa AF: 0.102 Hom.: 1942

Bravo AF: 0.118

Asia WGS AF: 0.200 AC: 694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.69
PhyloP100		-0.14
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: rs826221; hg19: chr3-24268436;