NM_001354712.2:c.-189+7916A>C

Variant names:

• chr3-24329384-T-G
• rs9812034
• NM_001354712.2:c.-189+7916A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354712.2(THRB):​c.-189+7916A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 152,068 control chromosomes in the GnomAD database, including 19,594 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 0.48 (19594 hom., cov: 33)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75
• Publications: 2 publications found

Genes affected

THRB (HGNC:11799): (thyroid hormone receptor beta) 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. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene. [provided by RefSeq, Jul 2008]

THRB Gene-Disease associations (from GenCC):

• thyroid hormone resistance, generalized, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hormone resistance, generalized, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.-189+7916A>C		intron_variant	Intron 2 of 10	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.-189+7916A>C		intron_variant	Intron 2 of 10		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73463 AN: 151950 Hom.: 19538 Cov.: 33

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.470

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.484 AC: 73582 AN: 152068 Hom.: 19594 Cov.: 33 AF XY: 0.486 AC XY: 36127 AN XY: 74338

African (AFR) AF: 0.687 AC: 28476 AN: 41476

American (AMR) AF: 0.573 AC: 8765 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1260 AN: 3472

East Asian (EAS) AF: 0.649 AC: 3357 AN: 5170

South Asian (SAS) AF: 0.459 AC: 2210 AN: 4814

European-Finnish (FIN) AF: 0.355 AC: 3755 AN: 10582

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24258 AN: 67948

Other (OTH) AF: 0.471 AC: 994 AN: 2112

Alfa AF: 0.397 Hom.: 21498

Bravo AF: 0.514

Asia WGS AF: 0.535 AC: 1860 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0080
DANN	Benign	0.73
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs9812034; hg19: chr3-24370875;