rs7642682

Positions:

• chr3-24373085-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354712.2(THRB):​c.-260-35714T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 151,920 control chromosomes in the GnomAD database, including 4,228 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 0.23 (4228 hom., cov: 32)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576

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]

ACMG classification

Verdict is Benign. Variant got -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 = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRB	NM_001354712.2	c.-260-35714T>A		intron_variant		ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.-260-35714T>A		intron_variant			NM_001354712.2	ENSP00000496686

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34318 AN: 151802 Hom.: 4216 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.226 AC: 34357 AN: 151920 Hom.: 4228 Cov.: 32 AF XY: 0.223 AC XY: 16559 AN XY: 74248

Gnomad4 AFR AF: 0.303

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.0335

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.215

Alfa AF: 0.215 Hom.: 459

Bravo AF: 0.227

Asia WGS AF: 0.152 AC: 527 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.55
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs7642682; hg19: chr3-24414576;