rs149579879

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003250.6(THRA):​c.1386C>G​(p.Asp462Glu) variant causes a missense 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

THRA
NM_003250.6 missense

Scores

1
6
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.450
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]
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]

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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 the THRA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.4693 (above the threshold of 3.09). Trascript score misZ: 4.2669 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital nongoitrous hypothryoidism 6.
BP4
Computational evidence support a benign effect (MetaRNN=0.08854127).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NR1D1NM_021724.5 linkc.1646-13G>C intron_variant Intron 7 of 7 ENST00000246672.4 NP_068370.1 P20393F1D8S3
THRANM_001190919.2 linkc.1386C>G p.Asp462Glu missense_variant Exon 10 of 10 NP_001177848.1 P10827-1
THRANM_003250.6 linkc.1386C>G p.Asp462Glu missense_variant Exon 10 of 10 NP_003241.2 P10827-1
THRANM_001190918.2 linkc.1269C>G p.Asp423Glu missense_variant Exon 10 of 10 NP_001177847.1 P10827-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
THRAENST00000264637.8 linkc.1386C>G p.Asp462Glu missense_variant Exon 10 of 10 1 ENSP00000264637.4 P10827-1
THRAENST00000584985.5 linkc.1269C>G p.Asp423Glu missense_variant Exon 10 of 10 1 ENSP00000463466.1 P10827-3
NR1D1ENST00000246672.4 linkc.1646-13G>C intron_variant Intron 7 of 7 1 NM_021724.5 ENSP00000246672.3 P20393
THRAENST00000394121.8 linkc.1386C>G p.Asp462Glu missense_variant Exon 10 of 10 2 ENSP00000377679.4 P10827-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250146
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135654
show subpopulations
Gnomad AFR exome
AF:
0.0000622
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.044
T
BayesDel_noAF
Benign
-0.12
CADD
Benign
15
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;.;T
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.35
.;T;T
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.089
T;T;T
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Benign
0.0
N;.;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.13
N;.;N
REVEL
Uncertain
0.40
Sift
Uncertain
0.0090
D;.;D
Sift4G
Pathogenic
0.0
D;T;D
Polyphen
0.17
B;B;B
Vest4
0.054
MutPred
0.21
Gain of glycosylation at S464 (P = 0.1444);.;Gain of glycosylation at S464 (P = 0.1444);
MVP
0.92
MPC
0.97
ClinPred
0.16
T
GERP RS
1.9
Varity_R
0.052
gMVP
0.13

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.

Other links and lift over

dbSNP: rs149579879; hg19: chr17-38249548; API