rs876657394

Positions:

• chr17-40089399-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The ENST00000450525.7(THRA):​c.1176C>A​(p.Cys392Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: THRA ENST00000450525.7 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.579

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0462 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-40089399-C-A is Pathogenic according to our data. Variant chr17-40089399-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 192271.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRA	NM_199334.5	c.1176C>A	p.Cys392Ter	stop_gained	9/9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.1176C>A	p.Cys392Ter	stop_gained	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:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital nongoitrous hypothyroidism 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Benign	0.060
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	0.89	D;D;D;D;D
Vest4		0.57
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs876657394; hg19: chr17-38245652;