rs12939700

Variant names:

• chr17-40089538-C-A
• rs12939700
• NM_199334.5:c.*82C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_199334.5(THRA):​c.*82C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,524,054 control chromosomes in the GnomAD database, including 2,715 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.073 (643 hom., cov: 31)
  • Exomes 𝑓: 0.050 (2072 hom.)
• Consequence: THRA NM_199334.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 11 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]

THRA Gene-Disease associations (from GenCC):

• congenital nongoitrous hypothyroidism 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRA	NM_199334.5	c.*82C>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.*82C>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_199334.5	ENSP00000395641.3

Frequencies

GnomAD3 genomes AF: 0.0727 AC: 11057 AN: 152000 Hom.: 635 Cov.: 31

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.0317

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0651

GnomAD4 exome AF: 0.0496 AC: 68022 AN: 1371936 Hom.: 2072 Cov.: 31 AF XY: 0.0484 AC XY: 32657 AN XY: 674662

African (AFR) AF: 0.156 AC: 4840 AN: 31026

American (AMR) AF: 0.0258 AC: 856 AN: 33200

Ashkenazi Jewish (ASJ) AF: 0.0296 AC: 646 AN: 21798

East Asian (EAS) AF: 0.00280 AC: 104 AN: 37164

South Asian (SAS) AF: 0.0380 AC: 2823 AN: 74214

European-Finnish (FIN) AF: 0.0473 AC: 2003 AN: 42314

Middle Eastern (MID) AF: 0.0153 AC: 68 AN: 4456

European-Non Finnish (NFE) AF: 0.0503 AC: 53825 AN: 1070904

Other (OTH) AF: 0.0502 AC: 2857 AN: 56860

GnomAD4 genome AF: 0.0730 AC: 11104 AN: 152118 Hom.: 643 Cov.: 31 AF XY: 0.0700 AC XY: 5206 AN XY: 74374

African (AFR) AF: 0.152 AC: 6316 AN: 41454

American (AMR) AF: 0.0357 AC: 546 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.00426 AC: 22 AN: 5166

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4822

European-Finnish (FIN) AF: 0.0439 AC: 466 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0491 AC: 3336 AN: 67990

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0543 Hom.: 222

Bravo AF: 0.0754

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		1.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12939700; hg19: chr17-38245791;