3-24214926-C-G

Variant names:

• chr3-24214926-C-G
• rs10510540
• NM_001354712.2:c.22+14012G>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+14012G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,210 control chromosomes in the GnomAD database, including 2,605 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 (2605 hom., cov: 32)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0300
• 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: SD, AD Classification: STRONG Submitted by: PanelApp Australia, 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.22+14012G>C		intron	N/A	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.22+14012G>C		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.22+14012G>C		intron	N/A	NP_001121648.1	P10828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.22+14012G>C		intron	N/A	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.22+14012G>C		intron	N/A	ENSP00000348827.4	P10828-1
	THRB	ENST00000447875.5	TSL:1	c.22+14012G>C		intron	N/A	ENSP00000388467.1	A0A0C4DG57

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16805 AN: 152092 Hom.: 2596 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.0598

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.0778

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

GnomAD4 genome AF: 0.111 AC: 16859 AN: 152210 Hom.: 2605 Cov.: 32 AF XY: 0.109 AC XY: 8101 AN XY: 74432

African (AFR) AF: 0.350 AC: 14516 AN: 41470

American (AMR) AF: 0.0495 AC: 757 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0891 AC: 462 AN: 5188

South Asian (SAS) AF: 0.0593 AC: 286 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00913 AC: 621 AN: 68022

Other (OTH) AF: 0.0770 AC: 163 AN: 2116

Alfa AF: 0.00510 Hom.: 4

Bravo AF: 0.127

Asia WGS AF: 0.0870 AC: 304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.0
DANN	Benign	0.71
PhyloP100		0.030
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: rs10510540; hg19: chr3-24256417;