NM_001354712.2:c.1144+9G>A

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: SD, AD Classification: STRONG Submitted by: PanelApp Australia, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354712.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.1144+9G>A		intron	N/A	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.1144+9G>A		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.1144+9G>A		intron	N/A	NP_001121648.1	P10828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.1144+9G>A		intron	N/A	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.1144+9G>A		intron	N/A	ENSP00000348827.4	P10828-1
	THRB	ENST00000280696.9	TSL:5	c.1189+9G>A		intron	N/A	ENSP00000280696.5	P10828-2

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	Thyroid hormone resistance, generalized, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

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;