Variant 17-40093039-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The ENST00000264637.8(THRA):c.1130C>T(p.Ser377Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

THRA
ENST00000264637.8 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.48

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:

NR1D1 (HGNC:7962): (nuclear receptor subfamily 1 group D member 1) This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes. [provided by RefSeq, Jan 2013]

NR1D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a domain NR LBD (size 244) in uniprot entity THA_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in ENST00000264637.8

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 4.2669 (greater than threshold 3.09). GenCC has associacion of gene with congenital nongoitrous hypothryoidism 6.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1D1	NM_021724.5 linkuse as main transcript	c.*44G>A		3_prime_UTR_variant	8/8	ENST00000246672.4	NP_068370.1
THRA	NM_199334.5 linkuse as main transcript			downstream_gene_variant		ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1D1	ENST00000246672.4 linkuse as main transcript	c.*44G>A		3_prime_UTR_variant	8/8	1	NM_021724.5	ENSP00000246672	P1
THRA	ENST00000450525.7 linkuse as main transcript			downstream_gene_variant		1	NM_199334.5	ENSP00000395641	P1	P10827-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Congenital nongoitrous hypothyroidism 6

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Sep 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

.;T

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

D;N;N;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.58

N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

0.96

D;D

Vest4

0.76

MutPred

0.59

Loss of disorder (P = 0.038);Loss of disorder (P = 0.038);

MVP

0.96

MPC

0.93

ClinPred

0.83

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.70

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

Other links and lift over