3-24117517-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001354712.2(THRB):c.*5367C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 152,266 control chromosomes in the GnomAD database, including 4,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (4949 hom., cov: 33)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: THRB NM_001354712.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.519

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-24117517-G-A is Benign according to our data. Variant chr3-24117517-G-A is described in ClinVar as [Benign]. Clinvar id is 344537.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.*5367C>T		3_prime_UTR_variant	11/11	ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.*5367C>T		3_prime_UTR_variant	11/11		NM_001354712.2
THRB	ENST00000396671.7	c.*5367C>T		3_prime_UTR_variant	10/10	5

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28711 AN: 152132 Hom.: 4927 Cov.: 33

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0951

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0706

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.125 AC: 2 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8

Gnomad4 ASJ exome AF: 0.00

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.189 AC: 28785 AN: 152250 Hom.: 4949 Cov.: 33 AF XY: 0.189 AC XY: 14047 AN XY: 74440

Gnomad4 AFR AF: 0.463

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0951

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0706

Gnomad4 OTH AF: 0.160

Alfa AF: 0.117 Hom.: 426

Bravo AF: 0.199

Asia WGS AF: 0.190 AC: 660 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.17
Dann	Benign	0.74

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: rs2167116; hg19: chr3-24159008;