rs3752874

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001354712.2(THRB):c.735C>T(p.Phe245Phe) 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

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

thyroid hormone resistance, generalized, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hormone resistance, generalized, autosomal recessive
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

THRB links:

THRB-AS2 (HGNC:):

THRB-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 198422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
THRB	NM_001354712.2 link	c.735C>T	p.Phe245Phe	synonymous_variant	Exon 8 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2 link	c.735C>T	p.Phe245Phe	synonymous_variant	Exon 8 of 11		NM_001354712.2	ENSP00000496686.2		P10828-1

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

GnomAD2 exomes

AF:

0.155

AC:

38775

AN:

250376

AF XY:

0.158

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 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

African (AFR)

AF:

0.139

AC:

4668

AN:

33474

American (AMR)

AF:

0.167

AC:

7449

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

5951

AN:

26136

East Asian (EAS)

AF:

0.0550

AC:

2182

AN:

39698

South Asian (SAS)

AF:

0.221

AC:

19089

AN:

86246

European-Finnish (FIN)

AF:

0.128

AC:

6813

AN:

53418

Middle Eastern (MID)

AF:

0.202

AC:

1166

AN:

5766

European-Non Finnish (NFE)

AF:

0.152

AC:

169215

AN:

1111748

Other (OTH)

AF:

0.160

AC:

9692

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

10955

21909

32864

43818

54773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6116

12232

18348

24464

30580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.151

AC:

22912

AN:

152214

Hom.:

1852

Cov.:

AF XY:

0.150

AC XY:

11143

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.146

AC:

6046

AN:

41532

American (AMR)

AF:

0.184

AC:

2811

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

809

AN:

3466

East Asian (EAS)

AF:

0.0570

AC:

295

AN:

5174

South Asian (SAS)

AF:

0.219

AC:

1057

AN:

4824

European-Finnish (FIN)

AF:

0.109

AC:

1159

AN:

10606

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.150

AC:

10223

AN:

68000

Other (OTH)

AF:

0.164

AC:

346

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1011

2023

3034

4046

5057

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.156

Hom.:

1728

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

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Thyroid hormone resistance, generalized, autosomal dominant

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.47

PhyloP100

1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over