rs13063628

Variant names:

• chr3-24127490-C-T
• rs13063628
• NM_001354712.2:c.1144+9G>A

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: -0.580
• Publications: 8 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.1144+9G>A		intron_variant	Intron 10 of 10	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.1144+9G>A		intron_variant	Intron 10 of 10		NM_001354712.2	ENSP00000496686.2

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

GnomAD2 exomes AF: 0.109 AC: 27376 AN: 250984 AF XY: 0.111

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 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

African (AFR) AF: 0.0588 AC: 1967 AN: 33474

American (AMR) AF: 0.0630 AC: 2817 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2836 AN: 26132

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0825 AC: 7116 AN: 86244

European-Finnish (FIN) AF: 0.169 AC: 9045 AN: 53412

Middle Eastern (MID) AF: 0.0937 AC: 540 AN: 5764

European-Non Finnish (NFE) AF: 0.147 AC: 163514 AN: 1111640

Other (OTH) AF: 0.123 AC: 7441 AN: 60388

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

African (AFR) AF: 0.0650 AC: 2697 AN: 41512

American (AMR) AF: 0.0821 AC: 1255 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.0679 AC: 327 AN: 4818

European-Finnish (FIN) AF: 0.169 AC: 1785 AN: 10562

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.148 AC: 10057 AN: 68008

Other (OTH) AF: 0.107 AC: 226 AN: 2116

Alfa AF: 0.126 Hom.: 2270

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 18, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Thyroid hormone resistance, generalized, autosomal dominant Benign:1

Jan 13, 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	-0.80
CADD	Benign	7.9
DANN	Benign	0.51
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13063628; hg19: chr3-24168981;