rs7609948

Positions:

• chr3-24124673-C-T

Variant summary

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

The NM_001354712.2(THRB):​c.1145-1548G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,090 control chromosomes in the GnomAD database, including 4,585 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 0.24 (4585 hom., cov: 32)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214

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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRB	NM_001354712.2	c.1145-1548G>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.1145-1548G>A		intron_variant			NM_001354712.2	ENSP00000496686

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36666 AN: 151972 Hom.: 4590 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.242

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

GnomAD4 genome AF: 0.241 AC: 36670 AN: 152090 Hom.: 4585 Cov.: 32 AF XY: 0.239 AC XY: 17805 AN XY: 74348

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.0505

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.238

Alfa AF: 0.254 Hom.: 1023

Bravo AF: 0.237

Asia WGS AF: 0.151 AC: 525 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.8
DANN	Benign	0.78

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: rs7609948; hg19: chr3-24166164;