3-24339895-T-G

Variant names:

• chr3-24339895-T-G
• rs7635707
• NM_001354712.2:c.-260-2524A>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.-260-2524A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 152,150 control chromosomes in the GnomAD database, including 20,892 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 0.51 (20892 hom., cov: 33)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354712.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.-260-2524A>C		intron	N/A	NP_001341641.1
	THRB	NM_000461.5		c.-114-2524A>C		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.-260-2524A>C		intron	N/A	NP_001121648.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.-260-2524A>C		intron	N/A	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.-260-2524A>C		intron	N/A	ENSP00000348827.4
	THRB	ENST00000447875.5	TSL:1	c.-251-2524A>C		intron	N/A	ENSP00000388467.1

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76774 AN: 152032 Hom.: 20858 Cov.: 33

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.534

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

GnomAD4 genome AF: 0.505 AC: 76867 AN: 152150 Hom.: 20892 Cov.: 33 AF XY: 0.507 AC XY: 37703 AN XY: 74388

African (AFR) AF: 0.676 AC: 28035 AN: 41494

American (AMR) AF: 0.623 AC: 9525 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1563 AN: 3472

East Asian (EAS) AF: 0.659 AC: 3407 AN: 5172

South Asian (SAS) AF: 0.480 AC: 2312 AN: 4820

European-Finnish (FIN) AF: 0.328 AC: 3481 AN: 10600

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26862 AN: 68000

Other (OTH) AF: 0.534 AC: 1127 AN: 2112

Alfa AF: 0.429 Hom.: 7395

Bravo AF: 0.539

Asia WGS AF: 0.533 AC: 1856 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.65
PhyloP100		2.2
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: rs7635707; hg19: chr3-24381386;