3-24227415-G-C

Variant names:

• chr3-24227415-G-C
• rs17014418
• NM_001354712.2:c.22+1523C>G

Variant summary

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

The NM_001354712.2(THRB):​c.22+1523C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 152,242 control chromosomes in the GnomAD database, including 358 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 0.064 (358 hom., cov: 32)
• Consequence: THRB NM_001354712.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 5 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: SD, AD Classification: STRONG Submitted by: PanelApp Australia, 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)

THRB-AS2 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0887 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.22+1523C>G		intron	N/A	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.22+1523C>G		intron	N/A	NP_000452.2
	THRB	NM_001128176.3		c.22+1523C>G		intron	N/A	NP_001121648.1	P10828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.22+1523C>G		intron	N/A	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.22+1523C>G		intron	N/A	ENSP00000348827.4	P10828-1
	THRB	ENST00000447875.5	TSL:1	c.22+1523C>G		intron	N/A	ENSP00000388467.1	A0A0C4DG57

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9816 AN: 152124 Hom.: 359 Cov.: 32

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0440

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.0544

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0683

Gnomad OTH AF: 0.0564

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

GnomAD4 genome AF: 0.0644 AC: 9811 AN: 152242 Hom.: 358 Cov.: 32 AF XY: 0.0646 AC XY: 4811 AN XY: 74434

African (AFR) AF: 0.0581 AC: 2412 AN: 41548

American (AMR) AF: 0.0439 AC: 672 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3472

East Asian (EAS) AF: 0.0547 AC: 283 AN: 5172

South Asian (SAS) AF: 0.0959 AC: 462 AN: 4818

European-Finnish (FIN) AF: 0.0907 AC: 963 AN: 10614

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0683 AC: 4646 AN: 68002

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0366 Hom.: 30

Bravo AF: 0.0597

Asia WGS AF: 0.0710 AC: 246 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.35
PhyloP100		0.12
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: rs17014418; hg19: chr3-24268906;