3-24352129-A-G

Variant names:

• chr3-24352129-A-G
• rs3951794
• NM_001354712.2:c.-260-14758T>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.-260-14758T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 152,030 control chromosomes in the GnomAD database, including 37,169 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 0.69 (37169 hom., cov: 33)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• Publications: 4 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=-0.78).
• 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.-260-14758T>C		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.-260-14758T>C		intron_variant	Intron 1 of 10		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104321 AN: 151912 Hom.: 37113 Cov.: 33

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.680

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

GnomAD4 genome AF: 0.687 AC: 104432 AN: 152030 Hom.: 37169 Cov.: 33 AF XY: 0.688 AC XY: 51088 AN XY: 74298

African (AFR) AF: 0.871 AC: 36158 AN: 41532

American (AMR) AF: 0.727 AC: 11091 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 1959 AN: 3472

East Asian (EAS) AF: 0.655 AC: 3382 AN: 5162

South Asian (SAS) AF: 0.661 AC: 3177 AN: 4806

European-Finnish (FIN) AF: 0.622 AC: 6571 AN: 10558

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.588 AC: 39966 AN: 67922

Other (OTH) AF: 0.676 AC: 1431 AN: 2116

Alfa AF: 0.637 Hom.: 9842

Bravo AF: 0.705

Asia WGS AF: 0.631 AC: 2194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		0.28
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: rs3951794; hg19: chr3-24393620;