rs2196427

Variant names:

• chr3-24491787-G-A
• rs2196427
• NM_001354712.2:c.-261+2865C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001354712.2(THRB):​c.-261+2865C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 152,062 control chromosomes in the GnomAD database, including 16,676 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 0.46 (16676 hom., cov: 33)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.574
• Publications: 5 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)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.521 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.-261+2865C>T		intron	N/A	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.-115+2865C>T		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.-261+2900C>T		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.-261+2865C>T		intron	N/A	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.-261+2900C>T		intron	N/A	ENSP00000348827.4	P10828-1
	THRB	ENST00000447875.5	TSL:1	c.-324+2900C>T		intron	N/A	ENSP00000388467.1	A0A0C4DG57

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70349 AN: 151944 Hom.: 16678 Cov.: 33

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.468

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

GnomAD4 genome AF: 0.463 AC: 70360 AN: 152062 Hom.: 16676 Cov.: 33 AF XY: 0.460 AC XY: 34197 AN XY: 74334

African (AFR) AF: 0.368 AC: 15251 AN: 41482

American (AMR) AF: 0.441 AC: 6748 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1776 AN: 3468

East Asian (EAS) AF: 0.397 AC: 2049 AN: 5160

South Asian (SAS) AF: 0.373 AC: 1793 AN: 4810

European-Finnish (FIN) AF: 0.512 AC: 5410 AN: 10576

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.526 AC: 35725 AN: 67972

Other (OTH) AF: 0.464 AC: 975 AN: 2100

Alfa AF: 0.496 Hom.: 27813

Bravo AF: 0.456

Asia WGS AF: 0.378 AC: 1314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.62
PhyloP100		0.57
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: rs2196427; hg19: chr3-24533278;