rs826221

chr3-24226945-A-G

Variant summary

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

The NM_001354712.2(THRB):c.22+1993T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 150,472 control chromosomes in the GnomAD database, including 1,281 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 0.11 (1281 hom., cov: 33)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.144

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.22+1993T>C		intron_variant		ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.22+1993T>C		intron_variant			NM_001354712.2
	ENST00000702841.1	n.268-33339A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16390 AN: 150352 Hom.: 1272 Cov.: 33

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0854

Gnomad OTH AF: 0.121

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

GnomAD4 genome AF: 0.109 AC: 16425 AN: 150472 Hom.: 1281 Cov.: 33 AF XY: 0.113 AC XY: 8302 AN XY: 73550

Gnomad4 AFR AF: 0.0770

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.0645

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.0854

Gnomad4 OTH AF: 0.128

Alfa AF: 0.0970 Hom.: 969

Bravo AF: 0.118

Asia WGS AF: 0.200 AC: 694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.2
Dann	Benign	0.69

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: rs826221; hg19: chr3-24268436;