3-24127623-C-T

Variant names:

• chr3-24127623-C-T
• rs121918688
• NM_001354712.2:c.1020G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001354712.2(THRB):​c.1020G>A​(p.Gln340Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: THRB NM_001354712.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 4 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)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP7: Synonymous conserved (PhyloP=2.77 with no splicing effect.

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.1020G>A	p.Gln340Gln	synonymous	Exon 10 of 11	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.1020G>A	p.Gln340Gln	synonymous	Exon 9 of 10	NP_000452.2
	THRB	NM_001128176.3		c.1020G>A	p.Gln340Gln	synonymous	Exon 10 of 11	NP_001121648.1	P10828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.1020G>A	p.Gln340Gln	synonymous	Exon 10 of 11	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.1020G>A	p.Gln340Gln	synonymous	Exon 10 of 11	ENSP00000348827.4	P10828-1
	THRB	ENST00000280696.9	TSL:5	c.1065G>A	p.Gln355Gln	synonymous	Exon 6 of 7	ENSP00000280696.5	P10828-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251472 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.9
DANN	Benign	0.77
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs121918688; hg19: chr3-24169114;