Variant 17-40084757-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2PP2PP5_ModerateBS2

The NM_199334.5(THRA):c.518A>G(p.Glu173Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

THRA
NM_199334.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.27

Variant links:

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]

THRA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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.

PP5

Variant 17-40084757-A-G is Pathogenic according to our data. Variant chr17-40084757-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 992628.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRA	NM_199334.5 linkuse as main transcript	c.518A>G	p.Glu173Gly	missense_variant	6/9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7 linkuse as main transcript	c.518A>G	p.Glu173Gly	missense_variant	6/9	1	NM_199334.5	ENSP00000395641	P1	P10827-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital nongoitrous hypothyroidism 6

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Charité Universitätsmedizin Berlin, Charite Universitaetsmedizin Berlin

Dec 01, 2020

The described THRA variant fulfills the PM2 criteria of the American College of Medical Genetics and Genomics classification (Richards et al. 2015) placing it in the 'likely pathogenic' category. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;D;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;.;D

M_CAP

Pathogenic

0.61

MetaRNN

Uncertain

0.54

D;D;D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.3

M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.5

D;.;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

D;.;D;D;D

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.67

P;P;P;.;.

Vest4

0.54

MutPred

0.23

Gain of MoRF binding (P = 0.05);Gain of MoRF binding (P = 0.05);Gain of MoRF binding (P = 0.05);Gain of MoRF binding (P = 0.05);Gain of MoRF binding (P = 0.05);

MVP

0.99

MPC

2.1

ClinPred

0.99

GERP RS

4.5

Varity_R

0.54

gMVP

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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