chr3-24378068-T-C

Variant names:

• chr3-24378068-T-C
• rs9809150
• NM_001354712.2:c.-260-40697A>G

Variant summary

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

The NM_001354712.2(THRB):​c.-260-40697A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 152,008 control chromosomes in the GnomAD database, including 39,765 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 0.72 (39765 hom., cov: 31)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 12 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.-260-40697A>G		intron_variant	Intron 1 of 10	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.-260-40697A>G		intron_variant	Intron 1 of 10		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109109 AN: 151890 Hom.: 39726 Cov.: 31

Gnomad AFR AF: 0.834

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.693

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

GnomAD4 genome AF: 0.718 AC: 109206 AN: 152008 Hom.: 39765 Cov.: 31 AF XY: 0.717 AC XY: 53259 AN XY: 74272

African (AFR) AF: 0.834 AC: 34604 AN: 41492

American (AMR) AF: 0.693 AC: 10570 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2124 AN: 3470

East Asian (EAS) AF: 0.577 AC: 2969 AN: 5148

South Asian (SAS) AF: 0.696 AC: 3356 AN: 4822

European-Finnish (FIN) AF: 0.695 AC: 7342 AN: 10566

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 46012 AN: 67944

Other (OTH) AF: 0.693 AC: 1462 AN: 2110

Alfa AF: 0.686 Hom.: 61864

Bravo AF: 0.720

Asia WGS AF: 0.603 AC: 2102 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.3
DANN	Benign	0.78
PhyloP100		0.0070
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: rs9809150; hg19: chr3-24419559;