rs1354053223

Positions:

• chr3-24127614-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001354712.2(THRB):​c.1029T>G​(p.Asn343Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N343T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: -0.446

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001354712.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THRB. . Gene score misZ 2.5652 (greater than the threshold 3.09). Trascript score misZ 3.708 (greater than threshold 3.09). GenCC has associacion of gene with thyroid hormone resistance, generalized, autosomal dominant, resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.1029T>G	p.Asn343Lys	missense_variant	10/11	ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.1029T>G	p.Asn343Lys	missense_variant	10/11		NM_001354712.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74172

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thyroid hormone resistance, generalized, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

May 06, 2008

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.93	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.73	N;N;N;N;N;N;N;N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.1	D;D;.;.;.;.;.;.;D;.;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0090	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Benign	1.0	T;T;.;.;.;.;.;.;T;.;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.90
MutPred		0.82		Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);Gain of ubiquitination at N343 (P = 0.0369);.;
MVP		0.45
MPC		1.9
ClinPred		0.59	D
GERP RS		-5.7
Varity_R		0.76
gMVP		0.87

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: rs1354053223; hg19: chr3-24169105;