NM_001354712.2:c.283+4390C>T

Variant names:

• chr3-24185684-G-A
• rs12639293
• NM_001354712.2:c.283+4390C>T

Variant summary

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

The NM_001354712.2(THRB):​c.283+4390C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 151,898 control chromosomes in the GnomAD database, including 11,153 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 0.37 (11153 hom., cov: 31)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.190
• Publications: 3 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-AS2 (HGNC:):

THRB-AS2 (HGNC:54854): (THRB antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.283+4390C>T		intron_variant	Intron 5 of 10	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.283+4390C>T		intron_variant	Intron 5 of 10		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56786 AN: 151780 Hom.: 11148 Cov.: 31

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.374 AC: 56820 AN: 151898 Hom.: 11153 Cov.: 31 AF XY: 0.374 AC XY: 27766 AN XY: 74244

African (AFR) AF: 0.497 AC: 20572 AN: 41384

American (AMR) AF: 0.336 AC: 5120 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1095 AN: 3466

East Asian (EAS) AF: 0.209 AC: 1077 AN: 5160

South Asian (SAS) AF: 0.379 AC: 1826 AN: 4812

European-Finnish (FIN) AF: 0.333 AC: 3511 AN: 10552

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22537 AN: 67952

Other (OTH) AF: 0.364 AC: 768 AN: 2108

Alfa AF: 0.345 Hom.: 15113

Bravo AF: 0.380

Asia WGS AF: 0.286 AC: 998 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.3
DANN	Benign	0.68
PhyloP100		0.19
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: rs12639293; hg19: chr3-24227175;