ENST00000264637.8:c.1386C>G

Variant names:

• chr17-40093295-C-G
• rs149579879
• ENST00000264637.8:c.1386C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000264637.8(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D462D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRA ENST00000264637.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.450
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 hypothyroidism 6.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08854127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D1	NM_021724.5	c.1646-13G>C		intron_variant	Intron 7 of 7	ENST00000246672.4	NP_068370.1
THRA	NM_001190919.2	c.1386C>G	p.Asp462Glu	missense_variant	Exon 10 of 10		NP_001177848.1
THRA	NM_003250.6	c.1386C>G	p.Asp462Glu	missense_variant	Exon 10 of 10		NP_003241.2
THRA	NM_001190918.2	c.1269C>G	p.Asp423Glu	missense_variant	Exon 10 of 10		NP_001177847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000264637.8	c.1386C>G	p.Asp462Glu	missense_variant	Exon 10 of 10	1		ENSP00000264637.4
THRA	ENST00000584985.5	c.1269C>G	p.Asp423Glu	missense_variant	Exon 10 of 10	1		ENSP00000463466.1
NR1D1	ENST00000246672.4	c.1646-13G>C		intron_variant	Intron 7 of 7	1	NM_021724.5	ENSP00000246672.3
THRA	ENST00000394121.8	c.1386C>G	p.Asp462Glu	missense_variant	Exon 10 of 10	2		ENSP00000377679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250146 AF XY: 0.00

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 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
PhyloP100		-0.45
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

Other links and lift over

dbSNP: rs149579879; hg19: chr17-38249548;