rs121918693

chr3-24127684-C-Achr3-24127684-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001354712.2(THRB):c.959G>T(p.Arg320Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 12 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, 2 uncertain in NM_001354712.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-24127685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, THRB
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 3-24127684-C-A is Pathogenic according to our data. Variant chr3-24127684-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12562.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.959G>T	p.Arg320Leu	missense_variant	10/11	ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.959G>T	p.Arg320Leu	missense_variant	10/11		NM_001354712.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Selective pituitary resistance to thyroid hormone Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L;L;L;L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.3	D;D;.;.;.;.;.;.;D;.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;D;.;D
Sift4G	Benign	0.16	T;T;.;.;.;.;.;.;T;.;T
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.
Vest4		0.97
MutPred		0.94		Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);Loss of glycosylation at P323 (P = 0.045);.;
MVP		0.96
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918693; hg19: chr3-24169175;