17-40089430-G-A

Position:

• chr17-40089430-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000450525.7(THRA):​c.1207G>A​(p.Glu403Lys) 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 (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: THRA ENST00000450525.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.63

Genes affected

THRA (HGNC:11796): (thyroid hormone receptor alpha) 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. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a domain NR LBD (size 244) in uniprot entity THA_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in ENST00000450525.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THRA. . Gene score misZ 3.4693 (greater than the threshold 3.09). Trascript score misZ 4.6029 (greater than threshold 3.09). GenCC has associacion of gene with congenital nongoitrous hypothryoidism 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 17-40089430-G-A is Pathogenic according to our data. Variant chr17-40089430-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 192272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRA	NM_199334.5	c.1207G>A	p.Glu403Lys	missense_variant	9/9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.1207G>A	p.Glu403Lys	missense_variant	9/9	1	NM_199334.5	ENSP00000395641	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2022	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25670821, 33509032) -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Jan 20, 2023	- -

Congenital nongoitrous hypothyroidism 6 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with congenital nongoitrous hypothyroidism 6 (MIM#614450) (PMID: 28932413). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There can be large variation in the severity of the phenotypes in RTHa as some patients can have mild phenotypes with minimal symptoms (PMID: 28932413). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated coactivator recognition site within the ligand binding domain of thyroid hormone receptor (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least three affected individuals (PMIDs: 26812777, 32349464, 33509032) and classified as pathogenic in ClinVar. (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.037	D;D
Vest4		0.59
MutPred		0.76		Gain of methylation at E403 (P = 0.0036);Gain of methylation at E403 (P = 0.0036);
MVP		0.96
ClinPred		0.88	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876657395; hg19: chr17-38245683; COSMIC: COSV52845965; COSMIC: COSV52845965;