3-24342514-C-T

Variant names:

• chr3-24342514-C-T
• rs9833191
• NM_001354712.2:c.-260-5143G>A

Variant summary

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

The NM_001354712.2(THRB):​c.-260-5143G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 151,992 control chromosomes in the GnomAD database, including 36,535 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 0.68 (36535 hom., cov: 31)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• 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: 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.-260-5143G>A		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.-260-5143G>A		intron_variant	Intron 1 of 10		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103198 AN: 151874 Hom.: 36475 Cov.: 31

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.680 AC: 103313 AN: 151992 Hom.: 36535 Cov.: 31 AF XY: 0.680 AC XY: 50470 AN XY: 74264

African (AFR) AF: 0.871 AC: 36106 AN: 41474

American (AMR) AF: 0.727 AC: 11110 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1978 AN: 3470

East Asian (EAS) AF: 0.645 AC: 3315 AN: 5140

South Asian (SAS) AF: 0.673 AC: 3238 AN: 4810

European-Finnish (FIN) AF: 0.587 AC: 6205 AN: 10564

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39201 AN: 67948

Other (OTH) AF: 0.672 AC: 1416 AN: 2108

Alfa AF: 0.642 Hom.: 50422

Bravo AF: 0.701

Asia WGS AF: 0.639 AC: 2220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.35
DANN	Benign	0.64
PhyloP100		-1.5
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: rs9833191; hg19: chr3-24384005;