chr3-24143504-G-A

Position:

chr3-24143504-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.64

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
THRB	NM_001354712.2 linkuse as main transcript	c.735C>T	p.Phe245=	synonymous_variant	8/11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2 linkuse as main transcript	c.735C>T	p.Phe245=	synonymous_variant	8/11		NM_001354712.2	ENSP00000496686		P10828-1
	ENST00000702841.1 linkuse as main transcript	n.83+5556G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

22919

AN:

152096

Hom.:

1854

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.157

AC XY:

114142

AN XY:

727112

show subpopulations

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.:

AF XY:

0.150

AC XY:

11143

AN XY:

74416

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over