rs3752874

Positions:

• chr3-24143504-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001354712.2(THRB):​c.735C>T​(p.Phe245=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,814 control chromosomes in the GnomAD database, including 20,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1852 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18266 hom.)
• Consequence: THRB NM_001354712.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.64

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-24143504-G-A is Benign according to our data. Variant chr3-24143504-G-A is described in ClinVar as [Benign]. Clinvar id is 198422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-24143504-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.735C>T	p.Phe245=	synonymous_variant	8/11	ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.735C>T	p.Phe245=	synonymous_variant	8/11		NM_001354712.2
	ENST00000702841.1	n.83+5556G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22919 AN: 152096 Hom.: 1854 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.0573

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.155 AC: 38775 AN: 250376 Hom.: 3277 AF XY: 0.158 AC XY: 21456 AN XY: 135410

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.0459

Gnomad SAS exome AF: 0.219

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.155 AC: 226225 AN: 1461600 Hom.: 18266 Cov.: 32 AF XY: 0.157 AC XY: 114142 AN XY: 727112

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.0550

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.151 AC: 22912 AN: 152214 Hom.: 1852 Cov.: 32 AF XY: 0.150 AC XY: 11143 AN XY: 74416

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.0570

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.164

Alfa AF: 0.155 Hom.: 1332

Bravo AF: 0.154

Asia WGS AF: 0.128 AC: 442 AN: 3478

EpiCase AF: 0.154

EpiControl AF: 0.156

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Thyroid hormone resistance, generalized, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	-0.51
CADD	Benign	9.6
DANN	Benign	0.47

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: rs3752874; hg19: chr3-24184995; COSMIC: COSV54981242; COSMIC: COSV54981242;