rs766183764

Variant names:

• chr17-40083899-G-A
• rs766183764
• NM_199334.5:c.287G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-40083899-G-A
• chr17-40083899-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_199334.5(THRA):​c.287G>A​(p.Cys96Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRA NM_199334.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.736

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 3 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: 4.6029 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital nongoitrous hypothryoidism 6.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRA	NM_199334.5	c.287G>A	p.Cys96Tyr	missense_variant	Exon 5 of 9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.287G>A	p.Cys96Tyr	missense_variant	Exon 5 of 9	1	NM_199334.5	ENSP00000395641.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251242 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135792

Gnomad AFR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

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	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;D;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.81	.;T;T;.;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.51	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Benign	2.0	M;M;M;M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N;.;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.089	T;.;T;T;T
Sift4G	Uncertain	0.038	D;D;D;D;D
Polyphen		0.95	P;P;P;.;.
Vest4		0.41
MutPred		0.51		Gain of phosphorylation at C96 (P = 0.0685);Gain of phosphorylation at C96 (P = 0.0685);Gain of phosphorylation at C96 (P = 0.0685);Gain of phosphorylation at C96 (P = 0.0685);Gain of phosphorylation at C96 (P = 0.0685);
MVP		0.96
MPC		2.7
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.88

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: rs766183764; hg19: chr17-38240152;