rs13063628

chr3-24127490-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001354712.2(THRB):c.1144+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,613,632 control chromosomes in the GnomAD database, including 15,393 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1116 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14277 hom.)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.580

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-24127490-C-T is Benign according to our data. Variant chr3-24127490-C-T is described in ClinVar as [Benign]. Clinvar id is 257669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-24127490-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.1144+9G>A		intron_variant		ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.1144+9G>A		intron_variant			NM_001354712.2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16805 AN: 152042 Hom.: 1116 Cov.: 32

Gnomad AFR AF: 0.0652

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0676

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.109 AC: 27376 AN: 250984 Hom.: 1831 AF XY: 0.111 AC XY: 15066 AN XY: 135718

Gnomad AFR exome AF: 0.0619

Gnomad AMR exome AF: 0.0599

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0810

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.134 AC: 195283 AN: 1461472 Hom.: 14277 Cov.: 34 AF XY: 0.132 AC XY: 96161 AN XY: 727076

Gnomad4 AFR exome AF: 0.0588

Gnomad4 AMR exome AF: 0.0630

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0825

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.110 AC: 16803 AN: 152160 Hom.: 1116 Cov.: 32 AF XY: 0.109 AC XY: 8074 AN XY: 74374

Gnomad4 AFR AF: 0.0650

Gnomad4 AMR AF: 0.0821

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0679

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.107

Alfa AF: 0.130 Hom.: 1744

Bravo AF: 0.101

Asia WGS AF: 0.0320 AC: 113 AN: 3478

EpiCase AF: 0.139

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Thyroid hormone resistance, generalized, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.80
Cadd	Benign	7.9
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs13063628; hg19: chr3-24168981;